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CYP3A

CYP3A is a major subfamily of the cytochrome P450 (CYP) superfamily of enzymes, consisting of heme-containing monooxygenases that primarily catalyze the oxidative metabolism of a wide range of endogenous and exogenous substrates.^[1] The subfamily includes four main isoforms in humans: CYP3A4, CYP3A5, CYP3A7, and CYP3A43, with CYP3A4 being the most abundant and functionally dominant in adults.^[2] These enzymes are predominantly expressed in the liver and small intestine, where they account for approximately 20–60% of total hepatic CYP content, playing a pivotal role in phase I drug metabolism by facilitating reactions such as hydroxylation, N-demethylation, and epoxidation.^[1] CYP3A enzymes metabolize over 50% of clinically used drugs, including statins, immunosuppressants, and anticancer agents, as well as endogenous compounds like steroid hormones, bile acids, and cholesterol.^[2] Their activity exhibits significant interindividual variability due to genetic polymorphisms (e.g., CYP3A5*3 allele reducing expression in certain populations), environmental factors, and drug interactions, where inhibitors like grapefruit juice or clarithromycin can reduce clearance and inducers like rifampicin can enhance it, leading to clinically significant pharmacokinetic alterations.^[3] In development, CYP3A7 predominates in fetal and neonatal liver, transitioning to adult patterns within the first year of life, with females often showing 20–30% higher CYP3A4 activity than males.^[1] Located on chromosome 7q21.3–q22.1, the CYP3A gene cluster's expression and function are regulated by nuclear receptors such as pregnane X receptor (PXR) and constitutive androstane receptor (CAR), underscoring their importance in toxicology, pharmacology, and personalized medicine.^[4]

Overview

Definition and Classification

The CYP3A subfamily belongs to the cytochrome P450 (CYP) superfamily, a group of heme-containing enzymes that primarily function as monooxygenases catalyzing oxidative metabolism of a wide range of substrates.^[5] These enzymes facilitate the addition of an oxygen atom to substrates, often as part of phase I drug metabolism, enabling detoxification or activation of compounds in the body.^[6] The CYP3A subfamily is particularly prominent due to its broad substrate specificity and high expression levels in key tissues.^[5] The CYP3A genes are clustered in a ~231 kbp region on chromosome 7q22.1, forming part of the CYP3A locus that includes four functional genes—CYP3A4, CYP3A5, CYP3A7, and CYP3A43—and two pseudogenes (CYP3A5P1 and CYP3A5P2).^[5]^[7]^[8] This genomic organization reflects the evolutionary conservation of the subfamily, with the functional genes encoding proteins that share high sequence similarity (typically >70% identity).^[8] The classification of CYP3A within the P450 superfamily follows the standardized nomenclature based on amino acid sequence homology, where "3" denotes the family and "A" the subfamily.^[3] CYP3A enzymes play a central role in metabolizing approximately 50% of clinically used drugs, as well as endogenous substrates such as steroids (e.g., testosterone, progesterone) and bile acids.^[9] They are predominantly expressed in the liver and small intestine, where they contribute to first-pass metabolism and systemic clearance of xenobiotics.^[5] This expression pattern underscores their importance in drug pharmacokinetics and potential for drug-drug interactions.^[5] The CYP3A subfamily was first identified in the 1980s through studies on human liver enzymes involved in steroid and xenobiotic oxidation, with the cDNA for the major isoform CYP3A4 cloned in 1986. Subsequent research in the late 1980s and early 1990s expanded understanding of the full gene cluster and its isoforms.^[5]

Subfamily Isoforms

The CYP3A subfamily in humans comprises four main isoforms: CYP3A4, CYP3A5, CYP3A7, and CYP3A43, each exhibiting distinct tissue-specific expression patterns and contributions to metabolic activity.^[5] These isoforms collectively account for a significant portion of cytochrome P450-mediated metabolism, with variations in abundance influencing drug disposition and endogenous processes.^[5] CYP3A4 is the predominant isoform in adults, representing approximately 85% of total CYP3A proteins and contributing 30–40% of overall hepatic cytochrome P450 content.^[5] It is highly expressed in the liver and small intestine, where it drives the majority of CYP3A-mediated activity, estimated at around 70% in hepatic contexts.^[10] Expression levels show substantial interindividual variability, ranging from tens- to hundreds-fold, influenced by factors such as age and genetic variants like CYP3A4*1B, which is more prevalent in African Americans (35–67%) compared to Caucasians (2–9%).^[5] CYP3A5, a closely related isoform, constitutes about 5% of total CYP3A proteins and is expressed in 10–30% of Caucasian livers due to polymorphisms such as CYP3A5*3, which leads to a nonfunctional protein in homozygous individuals.^[5] In populations of African or Asian descent, functional CYP3A5 expression is higher, occurring in 50–70% of individuals, with elevated levels in liver and intestine.^[5] Among expressers, CYP3A5 can contribute 10–50% of total CYP3A activity, particularly for substrates like tacrolimus, though its overall hepatic role is secondary to CYP3A4.^[11] It is also notable in extrahepatic tissues, including kidneys and lungs.^[5] CYP3A7 serves as the primary fetal and neonatal isoform, comprising roughly 3% of total CYP3A proteins in adults but dominating in the developing liver, where it accounts for 30–50% of total cytochrome P450 content.^[5] Expression is highest in fetal liver and intestines during the first trimester, supporting early steroid metabolism, with levels declining sharply postnatally to less than 1% in adults.^[5] Variability in fetal expression can span several hundred-fold among individuals.^[5] CYP3A43 is a minor isoform, making up about 6% of total CYP3A proteins, with low expression in the liver—approximately 15 times lower than CYP3A4—and limited metabolic contributions overall.^[5] It shows highest abundance in the prostate and brain (up to 170 times that of CYP3A4 in these tissues), as well as in kidney and pancreas, potentially playing a role in local steroid processing.^[5] mRNA levels vary up to 1,000-fold interindividually, particularly among Caucasians.^[5] The ontogeny of CYP3A isoforms reflects a developmental switch, with CYP3A7 predominating in embryonic, fetal, and early neonatal liver (high activity from the first trimester, comprising 87–100% of fetal CYP3A), followed by a rapid postnatal decline to near-undetectable levels within the first week.^[12] In contrast, CYP3A4 expression remains low prenatally but surges after birth, reaching 50% of adult levels by 6–12 months and becoming the dominant form in adulthood.^[12] CYP3A5 follows a similar postnatal increase, though with greater interindividual variability and no distinct developmental pattern in liver, while contributing more consistently in kidney.^[12] This transition underscores the adaptive shift in metabolic capacity from fetal-specific processes to adult drug and xenobiotic handling.^[12]

Genetics

Gene Organization

The CYP3A gene cluster is located on the long arm of human chromosome 7 at position 7q21.1-q22.1 and spans approximately 220-231 kb, containing four functional genes arranged in tandem: CYP3A5, CYP3A7, CYP3A4, and CYP3A43.^[13]^[14] This genomic organization reflects a series of ancient gene duplication events that expanded the cluster from an ancestral steroidogenic cytochrome P450 gene, leading to high evolutionary conservation across mammals.^[15] For instance, the amino acid sequences of CYP3A4 and CYP3A5 exhibit approximately 84% identity, underscoring their close phylogenetic relationship and shared functional roles in metabolism.^[16]^[17] Within the cluster, several pseudogenes, including CYP3A5P1 and CYP3A5P2, have arisen from additional duplication events but lack functional open reading frames and do not produce proteins.^[18] These non-functional copies, located between the active genes (e.g., between CYP3A5 and CYP3A7, and CYP3A4 and CYP3A7), contribute to the overall genetic complexity without influencing enzymatic activity.^[19] The genes in the CYP3A cluster share regulatory elements, such as proximal promoters and distal enhancers like the distal regulatory region (DRR), which facilitate co-regulation of expression across isoforms.^[20] These shared elements, including xenobiotic-responsive enhancers, allow coordinated transcriptional responses to environmental cues, promoting efficient control of the cluster's metabolic output.^[21]^[22]

Genetic Variations

The CYP3A gene cluster, located on chromosome 7q21.1, exhibits significant genetic variability that influences enzyme expression and function across individuals. Key polymorphisms in CYP3A4 and CYP3A5 are among the most studied, with the CYP3A53 allele (rs776746, 6986A>G) being a prominent example. This intronic variant introduces a premature stop codon via a splicing defect, resulting in a truncated, non-functional protein and absence of CYP3A5 expression in homozygous individuals. In Caucasian populations, the CYP3A53 allele frequency is approximately 0.93, leading to non-expression in about 90% of individuals.^[23] Similarly, the CYP3A4*22 allele (rs35599367, c.522-191C>T) is an intronic variant that reduces hepatic CYP3A4 mRNA and protein expression by roughly 50% through altered splicing efficiency, thereby decreasing overall enzymatic activity.^[24] Population differences in these variants contribute to inter-ethnic variability in CYP3A activity. CYP3A5 expressers, defined as carriers of at least one functional 1 allele, are far more prevalent in African populations (approximately 70%) compared to Europeans (about 10%), reflecting lower CYP3A53 allele frequencies in the former (0.17–0.21).^[25] In contrast, the CYP3A422 allele shows moderate frequencies across populations, around 5–7% in Europeans and lower in Asians and Africans. Additionally, the CYP3A71C variant (rs55785340, -76T>C in the promoter) disrupts a TATA box, leading to persistent CYP3A7 expression into adulthood in a subset of individuals, rather than the typical postnatal decline. This variant occurs at frequencies of 6–10% in various populations and is associated with continued low-level CYP3A7 activity in adult liver.^[26] These genetic variations have notable functional consequences, altering enzyme stability, catalytic activity, and substrate specificity. For instance, the CYP3A5*1 allele enhances the metabolism of certain substrates, such as increasing tacrolimus clearance by up to 50% in expressers compared to non-expressers, due to additive CYP3A5 contribution alongside CYP3A4.^[27] CYP3A4*22 carriers exhibit reduced clearance of CYP3A4-preferred substrates like simvastatin, stemming from lower enzyme levels and stability. Haplotype analysis within the CYP3A locus, particularly in the intergenic region between CYP3A7 and CYP3A4, further modulates expression; for example, the CYP3A7*1/CYP3A5*3 haplotype correlates with elevated CYP3A7 expression but absent CYP3A5, while variations in distal promoter elements can influence overall cluster-wide transcriptional output by 20–50%.^[14] Such haplotypes underscore the complex linkage disequilibrium in the region, impacting baseline CYP3A activity independently of individual SNPs.

Molecular Structure

Protein Architecture

The CYP3A subfamily consists of heme-thiolate proteins, each comprising approximately 500 amino acids and adopting the canonical cytochrome P450 fold, which features a compact globular architecture dominated by α-helices and β-sheets that envelop the heme prosthetic group.^[28] This overall fold is conserved across the family, with the N-terminal region forming a small β-sheet domain and the larger C-terminal domain comprising helical elements that create a central cavity for heme coordination. The structure supports the enzyme's role as a monooxygenase, with the heme group serving as the catalytic core.^[29] Key structural domains include the prominent α-helices D through K, which contribute to the helical bundle surrounding the active site, as well as five antiparallel β-sheets (β1-1 to β1-5) primarily in the N-terminal region that stabilize the overall scaffold.^[28] The heme is axially ligated by the sulfur atom of the conserved Cys442 residue embedded within the I-helix, a feature essential for electron transfer and oxygen activation in all CYP3A isoforms.^[28] Additional elements, such as the B-C loop and the F-G loop, impart flexibility to the structure, particularly over the substrate access channels. Crystal structures of the major isoforms CYP3A4 and CYP3A5 reveal nearly identical overall architectures, with root-mean-square deviation values below 1 Å for aligned Cα atoms, as exemplified by the 2.05 Å resolution structure of substrate-free CYP3A4 (PDB: 1TQN).^[28] Both isoforms exhibit a flexible lid formed by the F-G helices and connecting loop, which covers the spacious active site and enables conformational adaptability. Post-translational modifications vary among isoforms; for instance, CYP3A5 and CYP3A7 possess potential N-glycosylation sites at Asn139, which may modulate protein folding or membrane association, while all microsomal CYP3A enzymes are anchored to the endoplasmic reticulum via an N-terminal amphipathic α-helix that inserts into the lipid bilayer.^[30]

Substrate Binding Site

The substrate binding site of CYP3A enzymes, predominantly exemplified by CYP3A4, features a large, hydrophobic cavity that confers exceptional promiscuity for structurally diverse ligands. This cavity exhibits plasticity, with a volume expanding to approximately 1500–2000 Å³ upon ligand binding, far exceeding that of many other cytochrome P450s and allowing accommodation of substrates ranging from small molecules to bulky macrolides without rigid specificity constraints.^[31] The site's hydrophobic nature is dominated by aromatic and aliphatic residues, forming a flexible pocket that adapts through conformational shifts in helices F and G, as well as adjacent loops.^[31] Critical residues line the binding pocket and mediate substrate recognition via specific non-covalent interactions. Phenylalanines at positions 102, 110, and 304 contribute to π-stacking with aromatic substrate moieties, stabilizing planar ligands within the cavity.^[32] Complementarily, Arg105 engages in electrostatic and hydrogen bonding with polar groups, while Asn206 supports hydrogen bonding to enhance affinity for substrates bearing hydrogen bond acceptors or donors.^[33] These interactions, identified through site-directed mutagenesis and docking studies, underscore the site's versatility in orienting substrates proximal to the heme iron for oxidation.^[32] A hallmark of the CYP3A binding site is its capacity for cooperative binding, where multiple substrate molecules occupy the cavity simultaneously, often eliciting allosteric effects. Binding of one ligand can reshape the pocket to facilitate entry or optimal positioning of a second, enhancing catalytic efficiency; for instance, testosterone binding alters the site to boost midazolam metabolism rates via heterotropic cooperativity.^[34] This multisite occupancy, accommodating up to three testosterone molecules or stacked midazolam-testosterone pairs, arises from the site's malleability and peripheral allosteric regions near the F-G loop.^[32] X-ray crystallography has elucidated these features through high-resolution structures revealing open and closed conformations. In the CYP3A4-ketoconazole complex (2.8 Å resolution, PDB 2J0C), the inhibitor occupies a peripheral site while inducing cavity expansion and helix rearrangements, contrasting with more compact closed states in unliganded or progesterone-bound forms (e.g., PDB 1W0E).^[31] These structures confirm the site's dynamic accessibility, with root-mean-square deviations of 1.2–1.6 Å between conformations, highlighting conformational plasticity as key to substrate versatility.

Biochemical Function

Endogenous Substrates

CYP3A enzymes, particularly CYP3A4, play a pivotal role in the metabolism of endogenous steroid hormones, facilitating their inactivation and regulation of physiological processes such as hormone signaling and homeostasis. These enzymes catalyze the 6β-hydroxylation of testosterone, progesterone, and cortisol, among other reactions, which terminate androgenic and glucocorticoid activities in tissues like the prostate and liver. For instance, CYP3A4 performs 6β-, 2β-, 15β-, and 16β-hydroxylation of testosterone, while CYP3A5 and CYP3A7 contribute to 6β-, 2β-, and 2α-hydroxylation variants, thereby modulating prostate health and potentially influencing cancer progression. Similarly, progesterone undergoes 2β-, 6β-, 16α-, and 21-hydroxylation by CYP3A4, with 6β-hydroxylation by CYP3A5 and CYP3A7, supporting steroid balance influenced by hormonal feedback. Cortisol's 6β-hydroxylation by all three isoforms serves as a biomarker for glucocorticoid regulation via the 6β-hydroxycortisol/cortisol urinary ratio. Overall, CYP3A4 plays a major role in hepatic steroid catabolism, underscoring its importance in endogenous steroid metabolism.^[35] In bile acid metabolism, CYP3A enzymes contribute to cholesterol homeostasis by hydroxylating primary bile acids, enhancing their solubility and facilitating excretion. Specifically, CYP3A4 catalyzes the 6α-hydroxylation of chenodeoxycholic acid to hyodeoxycholic acid, a process that detoxifies potentially toxic bile acids like lithocholic acid through additional hydroxylation to more hydrophilic derivatives. This activity is regulated by nuclear receptors such as FXR and is crucial for preventing bile acid accumulation in the liver, with genetic polymorphisms in CYP3A potentially altering efficiency and impacting hepatobiliary function. CYP3A isoforms also metabolize vitamin D and lipids, influencing calcium balance, inflammation, and vascular tone. CYP3A4 acts as a 25-hydroxylase for vitamin D3 (cholecalciferol), converting it to 25-hydroxyvitamin D3, while also performing catabolic 24- and 25-hydroxylation of active 1,25-dihydroxyvitamin D3 to inactive forms, thereby fine-tuning vitamin D signaling and homeostasis. In lipid metabolism, CYP3A4 epoxidizes arachidonic acid to regioisomers of epoxyeicosatrienoic acids (EETs), such as 5,6-, 8,9-, 11,12-, and 14,15-EETs, which exert anti-inflammatory effects, promote vasodilation, and regulate cell proliferation, with implications for cardiovascular health and tumor angiogenesis. CYP3A4 also hydroxylates cholesterol to 4β-hydroxycholesterol, serving as a biomarker for CYP3A activity.^[36] Additionally, CYP3A enzymes participate in retinoic acid metabolism, which is essential for retinoid signaling in cell differentiation and development. CYP3A4 contributes to the 4-hydroxylation of all-trans-retinoic acid, forming 4-hydroxy-retinoic acid derivatives, while also supporting the formation of 18-hydroxy-retinoic acid, aiding in the clearance of this vitamin A derivative and modulating gene expression through interactions with nuclear receptors like RXR and CAR. These reactions ensure balanced retinoid levels, preventing dysregulation associated with developmental and proliferative disorders.

Xenobiotic Metabolism

CYP3A enzymes, particularly CYP3A4, play a central role in the phase I metabolism of xenobiotics, including a wide array of pharmaceuticals and environmental chemicals, by catalyzing oxidative reactions that facilitate their elimination. These enzymes are responsible for the biotransformation of approximately 50% of clinically used drugs, underscoring their prominence in drug metabolism.^[35] The broad substrate specificity of CYP3A allows it to accommodate diverse xenobiotics, ranging from small molecules to larger compounds, enabling efficient processing in both hepatic and extrahepatic tissues.^[36] The primary reactions mediated by CYP3A involve monooxygenation, utilizing molecular oxygen (O₂) and NADPH as cofactors to insert an oxygen atom into the substrate, often resulting in hydroxylation, N-dealkylation, or O-dealkylation. For instance, CYP3A4 oxidizes statins such as simvastatin to its major metabolite, 6'β-hydroxysimvastatin, which enhances solubility and excretion.^[37] Similarly, it catalyzes the N-demethylation of macrolide antibiotics like erythromycin, producing N-desmethylerythromycin as a key intermediate.^[38] Immunosuppressants such as cyclosporine undergo extensive CYP3A-mediated hydroxylation at multiple sites, contributing to their clearance.^[39] These transformations generally convert lipophilic xenobiotics into more polar, water-soluble metabolites, promoting their renal or biliary excretion and reducing potential toxicity. In addition to detoxification, CYP3A metabolism can generate reactive intermediates, as seen with acetaminophen, where CYP3A4 contributes to the formation of the electrophilic N-acetyl-p-benzoquinone imine (NAPQI), which requires conjugation with glutathione for safe elimination.^[40] CYP3A4 accounts for the metabolism of approximately 50% of clinically used drugs, with significant quantitative impact on pharmacokinetics.^[35] Intestinal CYP3A4, in particular, exerts a pronounced first-pass effect, substantially lowering the oral bioavailability of substrates like midazolam by pre-systemic oxidation in enterocytes.^[41] This intestinal barrier function further amplifies CYP3A's role in modulating systemic exposure to xenobiotics.

Regulation

Transcriptional Control

The transcriptional regulation of CYP3A genes is primarily mediated by the nuclear receptors pregnane X receptor (PXR, also known as NR1I2) and constitutive androstane receptor (CAR, NR1I3), which serve as sensors for xenobiotics and endogenous compounds. Upon ligand binding, PXR and CAR form heterodimers with the retinoid X receptor alpha (RXRα) and translocate to the nucleus, where they bind to specific response elements in the promoter regions of CYP3A genes, such as CYP3A4. Key response elements include the distal everted repeat with a 6-nucleotide spacer (ER6) and direct repeats with 3- or 4-nucleotide spacers (DR3/DR4), located in the proximal promoter and distal enhancers, thereby activating transcription and enabling adaptive responses to foreign chemicals.^[42] CAR exhibits similar binding affinity but with a preference for the proximal ER6 motif, contributing to isoform-specific regulation within the CYP3A family.^[43] Co-activators such as steroid receptor co-activator 1 (SRC-1) and peroxisome proliferator-activated receptor gamma co-activator 1-alpha (PGC-1α) enhance the transcriptional activity of ligand-bound PXR and CAR by facilitating chromatin remodeling and recruitment to CYP3A promoters. SRC-1 and PGC-1α interact with the activation function-2 (AF-2) domain of these receptors, amplifying induction up to 130-fold in the presence of ligands like rifampicin, as demonstrated in hepatocyte models.^[44] The CYP3A gene cluster on chromosome 7q21.1 features shared distal enhancers that coordinate expression across isoforms like CYP3A4 and CYP3A5, allowing synchronized regulation by PXR/CAR heterodimers binding to common response elements.^[45] Basal expression of CYP3A genes in the liver is driven by tissue-specific transcription factors, including hepatocyte nuclear factor 4-alpha (HNF4α) and CCAAT/enhancer-binding proteins (C/EBPα and C/EBPβ). HNF4α binds to DR1 motifs in the proximal promoter and distal enhancers (e.g., -237 to -211 bp and XREM at -7783 to -7771 bp), promoting constitutive transcription through interactions with co-activators like TET3, which induce histone modifications such as H3K4me1 and H3K27ac.^[43] C/EBP isoforms bind to sites in the proximal (-121 to -130 bp) and distal promoters (-1393 to -1402 bp, -1659 to -1668 bp), where the activating LAP forms of C/EBPβ stimulate expression, while repressive LIP forms inhibit it, fine-tuning hepatic levels. During development, a switch from fetal CYP3A7 to adult CYP3A4 expression occurs, influenced by promoter methylation: the CYP3A7 promoter remains hypomethylated in neonates to support high fetal expression, whereas CYP3A4 promoter CpG sites are hypermethylated early on and undergo demethylation postnatally to enable maturation-dependent activation.^[46] Endogenous feedback loops involving bile acids further modulate PXR activity to maintain homeostasis, as secondary bile acids like lithocholic acid (LCA) and its precursors act as ligands that activate PXR, inducing CYP3A expression for bile acid hydroxylation and detoxification. This PXR-CYP3A axis forms a negative feedback mechanism, where elevated bile acids trigger PXR-mediated transcription of CYP3A enzymes, which in turn metabolize the ligands to less toxic forms, preventing cholestatic liver injury.^[47]^[48]

Induction and Inhibition

CYP3A enzymes, particularly CYP3A4, can be induced by various xenobiotics through activation of nuclear receptors such as the pregnane X receptor (PXR). Rifampicin, a prototypical inducer, binds to PXR and promotes its translocation to the nucleus, where it heterodimerizes with the retinoid X receptor to drive transcription of CYP3A4, resulting in a 2- to 10-fold increase in enzyme expression and activity in human hepatocytes.^[49] St. John's wort, an herbal supplement, similarly induces CYP3A4 primarily through PXR activation by its component hyperforin, though some evidence suggests involvement of the constitutive androstane receptor (CAR) pathway in certain contexts.^[50] These induction processes are time-dependent, typically requiring hours for initial transcriptional activation and up to several days for maximal enzyme accumulation and functional upregulation.^[51] Inhibition of CYP3A occurs via multiple mechanisms, including reversible competitive binding and irreversible mechanism-based inactivation. Ketoconazole exemplifies competitive inhibition, binding directly to the CYP3A4 active site with a low dissociation constant (Ki ≈ 27 nM), thereby reducing substrate access without altering the enzyme structure.^[52] In contrast, mechanism-based inhibitors like the furanocoumarins (e.g., bergamottin) in grapefruit juice are metabolized by CYP3A4 to reactive intermediates that form covalent adducts with the enzyme, such as at residue Gln273, leading to permanent inactivation and loss of catalytic function.^[53] Reversible inhibitors dissociate upon removal, allowing rapid recovery of activity, whereas irreversible types necessitate new enzyme synthesis for restoration, often over days.^[54] The kinetics of CYP3A-mediated metabolism deviate from classical Michaelis-Menten behavior, especially with multiple substrates or effectors. For a single substrate, the reaction often follows Michaelis-Menten kinetics, where velocity increases hyperbolically with substrate concentration. However, CYP3A4 exhibits positive cooperativity when binding multiple ligands, modeled by the Hill equation with a Hill coefficient (n > 1, often ≈ 2), reflecting allosteric interactions within its large, flexible active site that enhance binding affinity for additional molecules.^[55] Isoform-specific differences influence inducibility and inhibition profiles. CYP3A5 is generally less inducible than CYP3A4 by prototypical agents like rifampicin, showing approximately 2-fold weaker upregulation due to differential promoter responsiveness to PXR and CAR. Inhibition similarly varies; for instance, ritonavir potently inhibits both isoforms but more effectively boosts bioavailability of co-administered drugs (e.g., protease inhibitors) by suppressing CYP3A4-dominated intestinal metabolism, increasing systemic exposure severalfold.^[56]^[57]

Clinical Significance

Drug Interactions

CYP3A enzymes, particularly CYP3A4 and CYP3A5, mediate the metabolism of approximately 50% of clinically used drugs, making them a primary locus for pharmacokinetic drug interactions. Inhibitors of CYP3A can substantially elevate plasma concentrations of substrate drugs, increasing the risk of toxicity, while inducers can reduce substrate levels, potentially leading to therapeutic failure. These interactions are particularly relevant for narrow therapeutic index drugs such as immunosuppressants, statins, and opioids, where even modest changes in exposure can precipitate adverse outcomes.^[9] A classic example of CYP3A inhibition involves ketoconazole, a strong inhibitor, which nearly triples the area under the curve (AUC) of cyclosporine, a key immunosuppressant, thereby heightening the risk of nephrotoxicity and requiring dose reductions of up to 80%. Similarly, co-administration of azole antifungals like itraconazole with statins such as simvastatin can elevate statin exposure severalfold, predisposing patients to rhabdomyolysis through myopathy. On the induction side, rifampicin, a potent CYP3A inducer, diminishes the efficacy of oral contraceptives by reducing ethinylestradiol and progestin levels by 50-60%, increasing the incidence of breakthrough ovulation and unintended pregnancies. For opioids like fentanyl, which are CYP3A substrates, concomitant use with inhibitors such as clarithromycin can prolong exposure and elevate overdose risk due to enhanced respiratory depression.^[58]^[59]^[60]^[61] Polypharmacy exacerbates these risks, with potential CYP-mediated interactions occurring in up to 80% of older adults taking five or more medications, many involving CYP3A substrates and modulators. In clinical settings, this contributes to adverse events in 20-30% of multi-drug regimens, such as statin-antifungal combinations leading to rhabdomyolysis or opioid-CYP3A inhibitor pairings resulting in overdose. The FDA classifies CYP3A inhibitors as strong (e.g., ketoconazole, itraconazole; ≥5-fold AUC increase in sensitive substrates) or moderate (e.g., erythromycin, fluconazole; 2- to <5-fold increase), guiding avoidance or monitoring for high-risk pairings. Management strategies include dose adjustments for substrates (e.g., reducing statin doses by 50-90% with strong inhibitors), therapeutic drug monitoring for agents like cyclosporine, and preferring non-CYP3A-dependent alternatives when possible.^[62]^[63] Special populations face amplified risks due to altered CYP3A expression. In the elderly, age-related changes including up to a 30% reduction in liver mass may contribute to declines in hepatic CYP3A activity, combined with polypharmacy, heighten substrate accumulation and inhibitor effects, increasing toxicity incidence.^[64] Patients with liver impairment exhibit proportionally diminished CYP3A capacity, exacerbating interactions; for instance, moderate inhibitors may cause greater-than-expected elevations in substrate levels compared to healthy individuals, necessitating cautious dosing and frequent monitoring.^[65]

Pharmacogenomics

Pharmacogenomics of the CYP3A subfamily plays a pivotal role in personalized medicine by elucidating how genetic variants influence drug metabolism, efficacy, and toxicity, enabling tailored dosing to optimize therapeutic outcomes and minimize adverse effects. Variations in CYP3A4 and CYP3A5 genes account for a substantial portion of inter-individual differences in drug clearance, with genetic factors contributing up to 30% of the variability in CYP3A-mediated metabolism.^[66] This is particularly relevant for drugs like immunosuppressants and statins, where precise dosing is critical to prevent rejection or cardiovascular events while avoiding overexposure. By integrating genotyping into clinical practice, pharmacogenomic strategies enhance patient safety and treatment response in diverse populations.^[67] CYP3A5 genotyping is essential for optimizing tacrolimus dosing in transplant recipients, as the enzyme significantly metabolizes this immunosuppressant. Individuals with the CYP3A5*1/1 genotype, classified as extensive metabolizers, exhibit rapid tacrolimus clearance and require 1.5- to 2-fold higher initial doses to achieve therapeutic trough levels, reducing the risk of graft rejection.^[68] Conversely, CYP3A53/*3 poor metabolizers display diminished enzyme activity, leading to higher tacrolimus concentrations at standard doses and an elevated risk of over-immunosuppression, including nephrotoxicity and infections.^[69] The Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines recommend genotype-based dose adjustments for tacrolimus, emphasizing pre-transplant testing to guide initial and maintenance therapy.^[70] Variants in CYP3A4, such as the *22 allele (rs35599367), impact statin pharmacokinetics and clinical outcomes. This decrease-of-function variant reduces CYP3A4 expression and enzyme activity, resulting in lower simvastatin clearance and elevated plasma concentrations.^[71] Consequently, carriers experience enhanced cholesterol-lowering efficacy due to increased drug exposure, though this may necessitate dose reductions to mitigate potential risks like myopathy, which is influenced by overall statin levels.^[72] Studies in large cohorts, such as the Cholesterol and Pharmacogenetics Study, confirm that CYP3A4*22 heterozygotes have approximately 20-30% higher simvastatin acid AUC, correlating with greater LDL cholesterol reduction but requiring monitoring for adverse muscular effects.^[71] Professional guidelines and regulatory labels incorporate CYP3A pharmacogenomics to inform dosing. While CPIC primarily addresses CYP3A5 for tacrolimus, emerging evidence highlights its role in drug-drug interactions with CYP3A substrates like voriconazole, where poor metabolizers may require adjusted doses to avoid supratherapeutic levels during co-administration.^[73] The U.S. Food and Drug Administration (FDA) product label for ticagrelor, a CYP3A4/5 substrate, warns of increased exposure with strong CYP3A inhibitors and decreased exposure with strong inducers, recommending avoidance of strong CYP3A modulators.^[74] Emerging research leverages polygenic risk scores (PRS) that combine CYP3A haplotypes with other variants to predict drug response variability, capturing 20-50% of differences in clearance for CYP3A-metabolized drugs like statins and antiretrovirals. These scores outperform single-variant models by accounting for cumulative genetic effects, improving precision in therapeutic predictions.^[66] Recent studies have integrated artificial intelligence (AI) with pharmacogenomic modeling and multi-omics data to enhance predictive accuracy in pharmacogenomics, with improvements of 5-20% over traditional methods.^[75] Such AI-assisted approaches hold promise for real-time clinical decision support in polypharmacy scenarios.

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The genetic determinants of the CYP3A5 polymorphism - PubMed
The frequencies of the g.6986A variant which allow for normal splicing of CYP3A5 transcripts are 5% in Caucasians, 29% in Japanese, 27% in Chinese, 30% in ...
[11]
Cytochrome P450 3A: ontogeny and drug disposition - PubMed - NIH
Ontogeny of CYP3A activity has been studied in vitro and in vivo. CYP3A7 activity is high during embryonic and fetal life and decreases rapidly during the first ...
[12]
Association of Genotypes of the CYP3A Cluster with Midazolam ...
The CYP3A gene cluster, which is located on chromosome 7q22 and spans ∼220 kb, consists of four genes including CYP3A4, CYP3A5, CYP3A7 and CYP3A43 (6).
[13]
Molecular Population Genetics of Human CYP3A Locus
The human CYP3A gene cluster resides in a 231-kb region on chromosome 7q22 and consists of four genes and two pseudogenes, arranged in the order of CYP3A5, ...Missing: span | Show results with:span
[14]
The human cytochrome P450 3A locus. Gene evolution by capture ...
Four CYP3A genes have been described in human, CYP3A4, CYP3A5, CYP3A7 (Nelson et al., 1996) and the recently discovered CYP3A43 (Domanski et al., 2001). CYP3A4 ...Missing: 97%
[15]
Effects of genetic polymorphism of cytochrome P450 enzymes on ...
Jul 17, 2007 · CYP3A5 has an 84% amino acid sequence similarity to CYP3A4 (17). The variability in CYP3A5 expression is caused mainly by the CYP3A5*3 ...
[16]
Cloning and tissue distribution of a novel human cytochrome p450 ...
It is concluded that CYP3A43 mRNA is expressed mainly in liver and testis and that the protein would not contribute significantly to human drug metabolism.Missing: history discovery 1989
[17]
Regulation of CYP3A4 and CYP3A5 by a lncRNA - NIH
The CYP3A locus contains four genes: CYP3A5, CYP3A7, CYP3A4, and CYP3A43. Gene orientation and the transcription start site are indicated. The expanded CYP3A4 ...
[18]
CYP3A5 - an overview | ScienceDirect Topics
Two non-processed pseudogenes exist (CYP3A5P1 and CYP3A5P2) in the regions between CYP3A5–CYP3A7 and CYP3A4–CYP3A7 respectively, also in head-to-tail ...
[19]
Regulatory variants in a novel distal enhancer regulate the ... - NIH
We hypothesized that distal enhancers regulate transcription of the four CYP3A genes in the CYP3A locus, and that this regulation may be dependent on varying ...
[20]
The far and distal enhancers in the CYP3A4 gene co-ordinate the ...
The far and distal enhancers in the CYP3A4 gene co-ordinate the proximal promoter in responding similarly to the pregnane X receptor but differentially to ...
[21]
Transcription Factors and ncRNAs Associated with CYP3A ... - MDPI
Nov 28, 2022 · Evidence suggests that the CYP3A gene cluster represents a regulome that is characterized by interacting enhancer/suppressor domains.
[22]
PharmVar GeneFocus: CYP3A5 - PMC
The CYP3A5*3 allele frequency is highest in Europeans and lowest in African American/Afro-Caribbeans and Sub-Saharan Africans, averaging 92%, 32%, and 24%, ...
[23]
CYP3A4 intronic SNP rs35599367 (CYP3A4*22) alters RNA splicing
We had demonstrated that an intronic single nucleotide polymorphism rs35599367 (CYP3A4*22, located in intron 6) reduces mRNA/protein expression; however, the ...
[24]
very important pharmacogene information for CYP3A5 - PMC - NIH
Together, CYP3A4 and CYP3A5 account for ~30% of hepatic cytochrome P450, and approximately half of the medications that are oxidatively metabolized by P450 are ...
[25]
Common Polymorphism in the CYP3A7 Gene Is Associated with a ...
Conclusion: The CYP3A7*1C polymorphism causes the persistence of enzymatic activity of CYP3A7 during adult life, resulting in lower circulating DHEAS and ...
[26]
Effect of CYP3A5 polymorphism on tacrolimus metabolic clearance ...
These data suggest that CYP3A5 contributes significantly to the metabolic clearance of tacrolimus in the liver and kidney.
[27]
The structure of human microsomal cytochrome P450 3A4 ... - PubMed
P450 3A4 catalyzes the metabolic clearance of a large number of clinically used drugs, and a number of adverse drug-drug interactions reflect the inhibition or ...
[28]
https://pubmed.ncbi.nlm.nih.gov/15258162/
[29]
CYP3A5 - Cytochrome P450 3A5 - Homo sapiens (Human) - UniProt
A cytochrome P450 monooxygenase involved in the metabolism of steroid hormones and vitamins (PubMed:10681376, PubMed:11093772, PubMed:12865317, ...
[30]
Structural basis for ligand promiscuity in cytochrome P450 3A4 | PNAS
Sep 12, 2006 · Here, we present crystal structures of human CYP3A4 in complex with two well characterized drugs: ketoconazole and erythromycin.
[31]
UNDERSTANDING THE MECHANISM OF CYTOCHROME P450 3A4
A remarkable feature of CYP3A4 is its extreme promiscuity in substrate specificity and cooperative substrate binding, which often leads to undesirable drug- ...
[32]
Structural basis for regiospecific midazolam oxidation by human ...
Dec 28, 2016 · Human cytochrome P450 3A4 (CYP3A4) is a major hepatic and intestinal enzyme that oxidizes more than 60% of administered therapeutics.Abstract · Sign Up For Pnas Alerts · Results And Discussion<|control11|><|separator|>
[33]
A NMR T1 Paramagnetic Relaxation Study | Biochemistry
These results suggest that the effector exerts its cooperative effects on MDZ metabolism through simultaneous binding of MDZ and effector near the CYP3A4 heme.
[34]
Comparative Metabolic Capabilities of CYP3A4, CYP3A5, and ...
The human cytochromes P450 (P450) CYP3A contribute to the biotransformation of 50% of oxidatively metabolized drugs. The predominant hepatic form is CYP3A4, ...
[35]
Structural Perspectives of the CYP3A Family and Their Small ... - NIH
CYP3A4 is considered the most important drug-metabolizing enzyme in the body and is the most abundant isoform in the liver, whereas CYP3A5 is the primary source ...
[36]
Simvastatin Pathway, Pharmacokinetics - ClinPGx
Both simvastatin and simvastatin acid are extensively metabolized by CYP3A4/5 to form 3-hydroxysimvastatin and 6-hydroxymethyl-simvastatin and -simvastatin acid ...
[37]
Erythromycin as a specific substrate for cytochrome P4503A ...
Erythromycin N-demethylation is catalyzed by cytochrome P4503A isozymes. By using [14C]methyl-labeled erythromycin, we were able to develop a N-demethylation ...
[38]
Functional evaluation of cyclosporine metabolism by CYP3A4 ... - NIH
CYP3A4 is the main metabolic pathway involved in the disposition of CsA. CsA shows genetic polymorphisms and can be induced and inhibited by other exogenous ...
[39]
Contribution of CYP2E1 and CYP3A to acetaminophen reactive ...
Background: CYP2E1, 1A2, and 3A4 have all been implicated in the formation of N-acetyl-p-benzoquinone imine (NAPQI), the reactive intermediate of acetaminophen ...
[40]
The effect of cytochrome P450 metabolism on drug ... - PubMed
Aug 1, 2007 · Although this class has more than 50 enzymes, six of them metabolize 90 percent of drugs, with the two most significant enzymes being CYP3A4 and ...
[41]
Prediction of human intestinal first-pass metabolism of 25 CYP3A ...
Intestinal first-pass metabolism may contribute to low oral drug bioavailability and drug-drug interactions, particularly for CYP3A substrates.
[42]
A Molecular Aspect in the Regulation of Drug Metabolism - NIH
PXR induces CYP gene expression by binding as heterodimers with the 9-cis retinoic acid receptor α (RXRα) to DR3, DR4, and ER6 motif in the proximal promoter ...
[43]
The Role of CYP3A in Health and Disease - MDPI
CYP3A is an enzyme subfamily in the cytochrome P450 (CYP) superfamily and includes isoforms CYP3A4, CYP3A5, CYP3A7, and CYP3A43.
[44]
Rifampicin Induction of CYP3A4 Requires PXR crosstalk with ... - NIH
Our study revealed that interaction of PXR with HNF4α and its co-activators PGC-1α and SRC-1 contributes to the strong induction of CYP3A4 by rifampicin and ...
[45]
Reciprocal activation of Xenobiotic response genes by nuclear ...
In a type of functional symmetry, orphan receptor CAR was also found to activate CYP3A through previously defined SXR/PXR response elements. These observations ...
[46]
Dynamics of Cytosine Methylation in the Proximal Promoters of ...
Methyl-seq anaylsis revealed that cytosines in the proximal promoter of CYP3A7 are hypomethylated in neonates compared with adolescents (P < 0.001). In contrast ...
[47]
Identification of bile acid precursors as endogenous ligands ... - PNAS
Expression of CYP3A is regulated in both species by the orphan nuclear pregnane X receptor (PXR), which is activated by a broad spectrum of xenobiotics ...
[48]
Nuclear receptors in bile acid metabolism - PMC - PubMed Central
The hydroxylation of bile acids is mediated mainly by CYP3A enzymes that are induced upon PXR activation (Staudinger et al., 2001). In addition, the bile acid ...Missing: loop | Show results with:loop
[49]
Roles of rifampicin in drug-drug interactions: underlying molecular ...
CYP3A4 is more efficiently induced than other CYPs [51,58-60]. In primary human hepatocytes, 20 microM rifampicin increased CYP3A4 mRNA by 14 fold, but CYP2B6 ...
[50]
St. John's wort induces hepatic drug metabolism through activation ...
In this report, we show that St. John's wort activates PXR and induces CYP3A4 expression in human hepatocytes. Moreover, we have identified hyperforin as the ...
[51]
When, Why and How to Conduct CYP2C Induction Studies | BioIVT
Apr 7, 2022 · ... induction can take hours to days to occur. This differs from direct enzyme inhibition, which can take seconds to minutes. Accordingly, it ...<|control11|><|separator|>
[52]
Inhibition of cytochrome P-450 3A (CYP3A) in human intestinal and ...
Ketoconazole exhibited a Ki for cDNA-expressed CYP3A4 of 26. 7 +/- 1.71 nM, whereas the Ki for cDNA expressed CYP3A5 was 109 +/- 19.7 nM. Corresponding Ki ...
[53]
Identification of the Residue in Human CYP3A4 That Is Covalently ...
Previous studies have demonstrated that bergamottin (BG), a component of grapefruit juice, is a mechanism-based inactivator of CYP3A4 and contributes, in part, ...
[54]
Inactivation of Cytochrome P450 3A4 by Bergamottin, a Component ...
These results indicate that BG, the primary furanocoumarin extracted from grapefruit juice, is a mechanism-based inactivator of P450 3A4. BG was also found to ...
[55]
Analysis of heterotropic cooperativity in cytochrome P450 3A4
The Hill coefficient (n = 2.04) indicated cooperative substrate binding, which was observed previously in cytochrome P450 monooxygenase reactions involved in ...
[56]
The Induction of Cytochrome P450 3A5 (CYP3A5) in the Human ...
The. CYP3A4 construct was activated 2–3-fold greater than CYP3A5 by CAR and PXR. Similarly, induction by rifampin was ⬃2-fold stronger. As with CYP3A5, ...
[57]
The Mechanism-Based Inactivation of CYP3A4 by Ritonavir - PMC
Aug 30, 2022 · Ritonavir is the most potent cytochrome P450 (CYP) 3A4 inhibitor in clinical use and is often applied as a booster for drugs with low oral ...
[58]
Drug Interactions in Solid Organ Transplant Recipients
Mar 5, 2017 · Ketoconazole has been shown to increase the AUC of cyclosporine by almost threefold, requiring up to an 80 % reduction in cyclosporine dose ...
[59]
Statins and CYP Interactions - Medsafe
Mar 6, 2014 · Simvastatin and atorvastatin, two widely prescribed cholesterol lowering medicines, are both metabolised by the isoenzyme cytochrome P450 3A4 (CYP3A4).
[60]
Roles of rifampicin in drug-drug interactions: underlying molecular ...
Feb 15, 2006 · It was found that concomitant administration of rifampicin and oral contraceptives could lead to failure of the antifertility effect of the ...
[61]
Opioid Therapies and Cytochrome P450 Interactions
Opioids are recognized as a necessary option for managing moderate-to-severe pain, yet many opioid side effects can be enhanced by metabolic interactions ...
[62]
Prevalence and Risk of Potential Cytochrome P450-Mediated Druh ...
Mar 12, 2013 · Results: The prevalence of potential CYP-mediated DDIs detected among 275 older adults with polypharmacy was 80%. The probability of at least 1 ...
[63]
Table of Substrates, Inhibitors and Inducers - Drug Interactions - FDA
Jun 5, 2023 · Strong and moderate inhibitors are drugs that increase the AUC ... Strong inhibitor of CYP2C19 and moderate inhibitor of CYP2C9 and CYP3A.In vitro marker reactions · In vitro selective inhibitors · Clinical index substrates
[64]
Aging‐Related CYP3A Functional Changes in Chinese Older ...
Jun 22, 2024 · Aging-related alterations in hepatic enzyme activity, particularly of the CYP3A, significantly impact drug efficacy and safety in older ...
[65]
Pharmacokinetic drug interactions in liver disease: An update - PMC
Clinical studies have shown that liver disease causes a reduction in the magnitude of interactions due to enzyme inhibition, which is proportional to the degree ...
[66]
The genetic landscape of major drug metabolizing cytochrome P450 ...
Sep 6, 2022 · Drug response can vary substantially between individuals with up to 50% of patients undergoing pharmacotherapy suffering from low treatment ...<|separator|>
[67]
Genotype-guided tacrolimus dosing in African American kidney ...
The guidelines recommend increasing the starting dose by 1.5–2 times in extensive metabolizers (CYP3A5*1/*1) and intermediate metabolizers (CYP3A5*1/*3, *1/*6, ...
[68]
[PDF] Clinical Pharmacogenetics Implementation Consortium (CPIC ...
CYP3A5*1/*3 is believed to explain up to 45% of the variability in tacrolimus dose.12 Because of the rarity of the CYP3A5*6 and CYP3A5*7 alleles in most.
[69]
POS-776 CYP3A5 POLYMORPHISMS ON TACROLIMUS DOSING ...
FAST metabolizers( *1/*1 ) required 1.5 to 2 times dosing compared to other two metabolizers .poor(*3/*3) metabolizers had tac related toxicity at similar dose ...
[70]
CPIC® Guideline for Tacrolimus and CYP3A5
Most recent guideline publication: Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for CYP3A5 genotype and Tacrolimus Dosing (July 2015)Missing: voriconazole | Show results with:voriconazole
[71]
CYP3A4*22 and CYP3A5*3 are associated with increased levels of ...
Observed differences in CYP3A allele frequencies and LD between African-Americans and Whites are consistent with previously reported allele frequency analyses ...
[72]
Genomewide Association Study of Simvastatin Pharmacokinetics
Jun 2, 2022 · The CYP3A4*22 (rs35599367) intron variant reduces CYP3A4 expression and associates with increased simvastatin exposure and cholesterol-lowering ...
[73]
CYP3A5 Genotype-Dependent Drug-Drug Interaction Between ...
Sep 13, 2023 · The objective of this study was to investigate whether CYP3A5 genotype could influence tacrolimus-voriconazole DDI in Chinese kidney transplant patients.
[74]
[PDF] BRILINTA® (ticagrelor) tablets, for oral use - accessdata.fda.gov
Strong CYP3A inducers substantially reduce ticagrelor exposure and so decrease the efficacy of ticagrelor. Avoid use with strong inducers of CYP3A (e.g. ...
[75]
Artificial Intelligence and Multi-Omics in Pharmacogenomics - NIH
Recently, multiple studies have found that integrating multi-omics with AI improves model performance across various pharmacogenomic applications. Table31 ...