Alternative titles; symbols
HGNC Approved Gene Symbol: CYP3A4
Cytogenetic location: 7q22.1 Genomic coordinates (GRCh38) : 7:99,756,967-99,784,184 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 7q22.1 | Vitamin D-dependent rickets, type 3 | 619073 | Autosomal dominant | 3 |
Cytochrome P450 3A4 (CYP3A4), the predominant P450 expressed in adult human liver, is both constitutively expressed and transcriptionally activated by a variety of structurally diverse xenochemicals. CYP3A4 is responsible for the oxidative metabolism of many clinically used drugs.
Watkins et al. (1985) identified a glucocorticoid-inducible cytochrome P450 in human liver. Molowa et al. (1986) reported the complete cDNA sequence of this P450. Wrighton and Vandenbranden (1989) isolated a CYP3-type cytochrome P450 from human fetal liver.
By somatic cell hybridization and in situ hybridization, Riddell et al. (1987) assigned to chromosome 7 the gene for a cytochrome P450 that encodes the enzyme nifedipine oxidase (CYP3). The assignment to chromosome 7 was corroborated by Gonzalez et al. (1988) by use of somatic cell hybrids. These authors also provided additional evidence supporting the identity of P450PCN1 and nifedipine oxidase.
By multipoint linkage analysis using DNA markers known to be located on chromosome 7, Brooks et al. (1988) concluded that the most likely location of CYP3 is 7q21-q22.1. No recombination with a COL1A2 (120160) marker was found. Spurr et al. (1989) assigned CYP3 to 7q22-qter by study of a panel of human-rodent somatic cell hybrids.
Inoue et al. (1992) mapped CYP3A4 to 7q22.1 by fluorescence in situ hybridization.
Shimada and Guengerich (1989) presented evidence that the major catalyst involved in the bioactivation of the hepatocarcinogen aflatoxin B(1) to its genotoxic 2,3-epoxide derivative is nifedipine oxidase, the P450 protein that also catalyzes the oxidation of nifedipine and other dihydropyridines, quinidine, macrolide antibiotics, various steroids, and other compounds. Levels of this P450 enzyme vary widely among humans, apparently in a broad unimodal distribution (Schellens et al., 1988). In vitro and in vivo evidence indicates that the enzyme can be induced by barbiturates, certain steroids, and macrolide antibiotics. Since the activity of the enzyme can be estimated by noninvasive assays, it may be feasible to test the hypothesis that liver cancer is linked to the level of oxidative metabolism in populations in which aflatoxin ingestion is high. Liver cancer, a major cause of premature death in many areas of Africa and Asia, has an incidence that is strongly correlated in those areas with exposure to aflatoxin B(1). AFB(1) is a mycotoxin produced by species of Aspergillus, and human exposure results principally from the ingestion of stored foodstuffs contaminated with the mold. Carcinogenicity is associated with its conversion to 8,9-oxide by the hepatic cytochrome P450-dependent monooxygenase system. Forrester et al. (1990) found that the rates of metabolic activation of AFB(1) were highly correlated with both the level of proteins of the CYP3A gene family and with the total cytochrome P450 content of the microsomes. Involvement of CYP1A2 (124060) and CYP2A1 (see 122720) was also found.
Daly et al. (1992), who referred to the gene as CYP3A4, pointed out that although Kleinbloesem et al. (1984) and Hoyo-Vadillo et al. (1989) described bimodal distributions for the metabolism of nifedipine, the bimodality could not be reproduced in studies of Renwick et al. (1988) and Schellens et al. (1988). In a study which had as its main purpose investigation of nifedipine metabolism in cystic fibrosis (219700), based on the fact that the CFTR (602421) and CYP3A4 loci are loosely linked, Daly et al. (1992) found in 59 controls a unimodal distribution of recoveries for the major metabolite of nifedipine, ranging from 33 to 78% excretion in 8 hours. In cystic fibrosis patients and their parents, the distribution of recoveries was shifted to the left, with 5 of 20 parents and 3 of 11 unrelated cystic fibrosis patients showing recoveries below the range observed in the control group. The poor metabolism appeared to be both reproducible and heritable.
Cytochrome P450 3A4 is one of the most abundant P450s in human liver (Wrighton and Stevens, 1992). It is inducible by a variety of agents including glucocorticoids and phenobarbital. It appears to play a central role in the metabolism of the immunosuppressive cyclic peptide cyclosporin A as well as macrolide antibiotics, such as erythromycin. It also catalyzes the 6-beta-hydroxylation of a number of steroids including testosterone, progesterone, and cortisol. As indicators of CYP3A4 function in the evaluation of transplant recipients, measurement of erythromycin metabolism by a breath test (Elshourbagy and Guzelian, 1980) and the presence of 6-beta-hydroxylated steroids in urine have been used. Shet et al. (1993) reported the results of experiments designed to evaluate the enzymatic properties of a purified recombinant fusion protein containing the heme domain of human CYP3A4. Reasons to doubt the validity of the in vivo tests of CYP3A4 activity were presented.
A single glass of grapefruit juice has been shown to increase significantly the oral availability of a variety of commonly used medications, including felodipine, nifedipine, verapamil, ethinylestradiol, and cyclosporin A. The mechanism of this effect is presumed to involve inhibition of metabolism rather than improved absorption, since many of the drugs affected appear to be well absorbed when taken in the absence of grapefruit juice. Most of the drugs affected by grapefruit juice are known to be primarily metabolized by CYP3A4, the most abundant cytochrome P450 in both the liver and in the enterocytes that line the lumen of the small bowel. Lown et al. (1997) noted several lines of evidence suggesting that the major site of CYP3A4 inhibition by grapefruit juice is the intestine rather than the liver. First, some drugs affected by grapefruit juice have been shown to undergo substantial metabolism by CYP3A4 in the small bowel. In addition, grapefruit juice does not appear to influence the clearance of CYP3A4 substrates when they are administered intravenously. Finally, the primary effect of grapefruit juice on orally administered medications is to increase peak serum concentration with little change in the subsequent rate of elimination as measured by half-life. Lown et al. (1997) evaluated the effect of repeated grapefruit juice ingestion on CYP3A4 expression in 10 healthy men who were given 8 ounces of grapefruit juice 3 times a day for 6 days. They found that grapefruit juice did not alter liver CYP3A4 activity, colon levels of CYP3A5, or small bowel concentrations of P-glycoprotein, villin, CYP1A1, and CYP2D6. In contrast, the concentration of CYP3A4 in enterocytes fell 62% with no corresponding change in CYP3A4 mRNA levels. In addition, enterocyte concentrations of CYP3A4 measured before grapefruit juice consumption correlated with the increase in peak serum concentration when felodipine was taken with either the first or the sixteenth glass of grapefruit juice relative to water. Lown et al. (1997) concluded that a mechanism for the effect of grapefruit juice on oral felodipine kinetics is its selective downregulation of CYP3A4 in the small intestine. There was no diminution in the effect of grapefruit juice over time. They observed downregulation of CYP3A5 protein as well as CYP3A4 protein.
St. John's wort is a popular herbal product used to treat depression and thought to be implicated in drug interactions. Markowitz et al. (2003) found that a 14-day course of St. John's wort administration significantly induced the activity of CYP3A4 as measured by changes in the pharmacokinetics of alprazolam. This suggested that long-term administration of St. John's wort may result in diminished clinical effectiveness or increased dosage requirement for all CYP3A4 substrates, which were said to represent at least 50% of all marketed medications.
Dimaraki and Jaffe (2003) examined the effects of troglitazone on the activity of hepatic CYP3A4 and the screening tests for Cushing syndrome (219080, 219090). They found that troglitazone induced the activity of CYP3A4, leading to a falsely abnormal dexamethasone suppression test, and suggested that the hydrocortisone suppression test is a useful alternative to the dexamethasone suppression test in patients taking medications that increase the activity of CYP3A4.
Gupta et al. (2004) found that CYP3A4, the most abundant cytochrome P450 enzyme in human liver and intestine, showed 7-fold greater activity than any of the other enzymes with 1-alpha-hydroxyvitamin D(2) as substrate. It was less active against 1-alpha-hydroxyvitamin D(3) and vitamin D(2), and it did not utilize vitamin D(3) as substrate. The 25-hydroxylase activity correlated with CYP3A4 testosterone 6-beta-hydroxylase activity, and CYP3A4 inhibitors inhibited 25-hydroxylase activity in recombinant CYP3A4 and pooled liver microsomes.
Crystal Structure
Williams et al. (2004) reported 3 crystal structures of CYP3A4: unliganded, bound to the inhibitor metyrapone, and bound to the substrate progesterone. The structures revealed a surprisingly small active site, with little conformational change associated with the binding of either compound. An unexpected peripheral binding site was identified, located above a phenylalanine cluster, which may be involved in the initial recognition of substrates or allosteric effectors.
Ekroos and Sjogren (2006) presented crystal structures of human CYP3A4 in complex with 2 well characterized drugs, ketoconazone and erythromycin, and thus provided a structural basis for the ability of CYP3A4 to contribute to the metabolism of more than half of marketed drugs. CYP3A4 underwent dramatic conformational changes upon ligand binding, with an increase in active-site volume of more than 80%. The structures represented 2 distinct open conformations of CYP3A4, because ketoconazone and erythromycin induced different types of coordinated shifts. There was also clear indication of multiple binding modes for erythromycin.
CYP3A4 is responsible for the oxidative metabolism of a wide variety of xenobiotics, including an estimated 60% of all clinically used drugs. Although expression of the CYP3A4 gene is known to be induced in response to a variety of compounds, the mechanism underlying this induction, which represents a basis for drug interactions in patients, was not clear. Lehmann et al. (1998) identified a human orphan nuclear receptor, termed the pregnane X receptor (PXR; 603065), that binds to a response element in the CYP3A4 promoter and is activated by a range of drugs known to induce CYP3A4 expression. Comparison of human PXR with mouse Pxr revealed marked differences in their activation by certain drugs, which may account in part for the species-specific effects of compounds on CYP3A4 gene expression. These findings provided a molecular explanation for the ability of disparate chemicals to induce CYP3A4 levels and, furthermore, provided a basis for developing in vitro assays to aid in predicting whether drugs will interact in humans.
Alteration in the activity or expression of CYP3A4 seems to be a key predictor of drug responsiveness and toxicity (Thummel and Wilkinson, 1998). Goodwin et al. (1999, 2002) showed that the ligand-activated nuclear receptors PXR and constitutive androstane receptor (CAR; 603881) regulate CYP3A4 expression. However, in cell-based reporter assays, CYP3A4 promoter activity was most pronounced in liver-derived cells and minimal or modest in nonhepatic cells, indicating that a liver-specific factor is required for physiologic transcriptional response. Tirona et al. (2003) showed that the orphan nuclear receptor hepatocyte nuclear factor-4-alpha (HNF4A; 600281) is critically involved in the PXR- and CAR-mediated transcriptional activation of CYP3A4. They identified a specific cis-acting element in the CYP3A4 gene enhancer that confers HNF4-alpha binding and thereby permits PXR- and CAR-mediated gene activation. Fetal mice with conditional deletion of Hnf4-alpha had reduced or absent expression of CYP3A. Furthermore, adult mice with conditional hepatic deletion of the gene had reduced basal and inducible expression of CYP3A. These data identified HNF4-alpha as an important regulator of coordinate nuclear receptor-mediated response to xenobiotics.
Masuyama et al. (2003) examined the expression and potential role of the PXR-CYP3A pathway in endometrial cancer tissues. Tissues showing high PXR expression showed significantly high expression of PXR targets CYP3A4 and CYP3A7 (605340) and low expression of the estrogen receptor (ER; see 133430) compared with levels in tissues showing low PXR expression. Among endometrial cancer cell lines, HEC-1 cells, which express high PXR and low ER and progesterone receptor (607311), showed a stronger transcriptional response of the PXR-CYP3A pathway to PXR ligands than did Ishikawa cells, which express low PXR but high ER. The authors concluded that steroid/xenobiotics metabolism in tumor tissue through the PXR-CYP3A pathway might play an important role as an alternative pathway for gonadal hormone and endocrine-disrupting chemical effects on endometrial cancer expressing low ER-alpha.
Gupta et al. (2005) screened 16 hepatic recombinant microsomal cytochrome P450 enzymes expressed in baculovirus-infected insect cells for 24-hydroxylase activity. CYP3A4, a vitamin D-25-hydroxylase, and CYP1A1 (108330) had the highest 24-hydroxylase activity with 1-alpha-hydroxyvitamin D2 (1-alpha-OHD2) as substrate. Rates of 24- and 25-hydroxylation of 1-alpha-OHD2 and 1-alpha-OHD3 were determined in recombinant wildtype CYP3A4 and site-directed mutants and naturally occurring variants expressed in Escherichia coli. Substitution of residues showed the most prominent alterations of function at residues 119, 120, 301, 305, and 479. Thus, CYP3A4 is both a 24- and 25-hydroxylase for vitamin D2, 1-alpha-OHD2, and 1-alpha-OHD3.
Association with Drug Metabolism
Distinct phase I and phase II pathways of drug metabolism comprise a protective mechanism against environmental toxins. Phase I metabolism by cytochrome P450 enzymes converts many compounds to reactive, electrophilic, water-soluble intermediates, some of which can damage DNA. The glutathione S-transferases (e.g., GSTP1, 134660) and N-acetyltransferases (e.g., NAT1, 108345), which are phase II enzymes, inactivate various toxic compounds, including compounds produced by phase I metabolism. Polymorphisms of potential relevance to chemical carcinogenesis are known for various cytochrome P450, glutathione S-transferase, and N-acetyltransferase enzymes. For example, a CYP2D6 polymorphism (124030) was found by Wolf et al. (1992) to be associated with an increased risk of leukemia; the poor metabolizer phenotype (see 608902) was thought to decrease the ability to detoxify chemical carcinogens. An excess of the GSTT1 (600436) null genotype was observed in an adult white population with myelodysplastic syndrome, again suggesting that decreased detoxification of carcinogens may enhance susceptibility to myelodysplastic syndrome (Chen et al., 1996). Epipodophyllotoxins, which are used as DNA topoisomerase II inhibitors in the treatment of leukemia and are associated with the production of translocations involving the MLL gene as well as of other translocations, are substrates for metabolism by CYP3A. Rebbeck et al. (1998) identified a variant in the 5-prime promoter region of the CYP3A4 gene: a polymorphism in the nephedipine-specific response element of the gene. They referred to the polymorphism as CYP3A4-V (124010.0001).
Felix et al. (1998) investigated genetic variation in drug metabolism as a potential host risk factor for leukemias induced by DNA topoisomerase II inhibitors. They examined the CYP3A4-V polymorphism in 99 de novo and 30 treatment-related leukemias. In all treatment-related cases, there was prior exposure to one or more anticancer drugs metabolized by CYP3A. Nineteen of 99 de novo (19%) and 1 of 30 treatment-related (3%) leukemias carried the CYP3A4-V polymorphism. Nine of 42 de novo leukemias with MLL gene translocations (21%), and 0 of 22 treatment-related leukemias with MLL gene translocations carried the CYP3A4-V polymorphism. This relationship remained significant when 19 treatment-related leukemias with MLL gene translocations that followed epipodophyllotoxin exposure were compared with the same 42 de novo cases. These data suggested that individuals with the CYP3A4-W (wildtype) genotype may be at increased risk for treatment-related leukemia and that epipodophyllotoxin metabolism of CYP3A4 may contribute to the secondary cancer risk. The CYP3A4-W genotype may increase production of potentially DNA-damaging reactive intermediates. The variant may decrease production of the epipodophyllotoxin catechol metabolite, which is the precursor of the potentially DNA-damaging quinone.
By genotyping liver samples from 18 Caucasian donors at 2 SNPs (78013C-T and 78649C-T) in intron 7 of CYP3A4, Hirota et al. (2004) demonstrated a correlation between the total CYP3A4 mRNA level and allelic expression ratio, defined as the relative transcript level ratio derived from the 2 alleles. Individuals with a low expression ratio, exhibiting a large difference of transcript level between the 2 alleles, revealed extremely low levels of total hepatic CYP3A4 mRNA, and thus low metabolic capability as assessed by testosterone 6-beta-hydroxylation.
Association with Susceptibility to Prostate Cancer
There are several pathways involved in the metabolism of testosterone, and the genes that regulate these pathways, including 5-alpha-reductase-2 (SRD5A2; 607306) and CYP3A4, have been implicated in prostate cancer (176807) susceptibility. The CYP3A4*1B allele (124010.0001) may decrease the oxidative deactivation of testosterone (Rebbeck et al., 1998). African Americans have the highest documented rates of prostate cancer in the world. Zeigler-Johnson et al. (2002) studied differences in genotypes at the SRD5A2 and CYP3A4 loci according to ethnicity. They found that the CYP3A4*1B allele was more common in Ghanaians and African Americans (gene frequency more than 50%) than in Caucasians (less than 10%), and was apparently nonexistent in Asians.
In a genotype/haplotype association study involving a case-control sample of 1,117 brothers from 506 sibships with prostate cancer, Loukola et al. (2004) detected associations between prostate cancer risk or aggressiveness and a number of CYP3A4 SNPs (p values between 0.006 and 0.05) and a CYP3A4 haplotype (p = 0.05 and 0.009 in nonstratified and stratified analyses, respectively). They noted that the CYP3A4*1B allele and the CYP3A4_Hap4 haplotype were inversely associated with low disease aggressiveness (p = 0.009 for both).
Vitamin D-Dependent Rickets, Type 3
Schirmer et al. (2006) investigated the CYP3A locus in 5 ethnic groups. The degree of linkage disequilibrium (LD) differed among ethnic groups, but the most common alleles of the conserved LD regions were remarkably similar. Non-African haplotypes were few; for example, only 4 haplotypes accounted for 80% of common European Caucasian alleles. Large LD blocks of high frequencies suggested selection. European Caucasian and Asian cohorts each contained a block of single-nucleotide polymorphisms with very high P excess values. The overlap between these blocks in these 2 groups contained only 2 of the investigated 26 SNPs, and 1 of them was the CYP3A4*1B allele. The region centromeric of CYP3A4*1B on 7q exhibited high haplotype homozygosity in European Caucasians as opposed to African Americans. CYP3A4*1B showed a moderate effect on CYP3A4 mRNA and protein expression, as well as on CYP3A activity assessed as V(max) of testosterone 6-beta-hydroxylation in a liver bank. Selection against the CYP3A4*1B allele in non-African populations was suggested. The elimination of this allele involved different parts of the CYP3A locus in European Caucasians and Asians. Because CYP3A4 is involved in vitamin D metabolism, Schirmer et al. (2006) raised the possibility that rickets might be the underlying selecting factor.
In 2 unrelated girls with vitamin D-dependent rickets (VDDR3; 619073), who were negative for mutation in known VDDR-associated genes, Roizen et al. (2018) identified heterozygosity for the same missense mutation in the CYP3A4 gene (I301T; 124010.0002). The mutation segregated with disease in both families and was not found in control exomes or public variant databases. In vitro experiments showed the I301T variant to have gain-of-function effects.
Paolini et al. (1999) found significant increases in the carcinogen-metabolizing enzymes CYP1A1 (108330), CYP1A2 (124060), CYP3A, CYP2B (123930), and CYP2A in the lungs of rats supplemented with high doses of beta-carotene. The authors suggested that correspondingly high levels of CYPs in humans would predispose an individual to cancer risk from the widely bioactivated tobacco-smoke procarcinogens, thus explaining the cocarcinogenic effect of beta-carotene in smokers.
The induction of CYP3A enzymes is species-specific and believed to involve 1 or more cellular factors, or receptor-like xenosensors. Xie et al. (2000) identified PXR/SXR (603065) as one such factor. They showed that targeted disruption of the mouse Pxr gene abolished induction of CYP3A by prototypic inducers such as dexamethasone or pregnenolone-16-alpha-carbonitrile. In Pxr-null mice carrying a transgene for an activated form of human SXR, there was constitutive upregulation of CYP3A gene expression and enhanced protection against toxic xenobiotic compounds. Xie et al. (2000) demonstrated that species origin of the receptor, rather than the promoter structure of the CYP3A genes, dictates the species-specific pattern of CYP3A inducibility. Thus, they could generate 'humanized' transgenic mice that were responsive to human-specific inducers such as the antibiotic rifampicin. Xie et al. (2000) concluded that the SXR/PXR genes encode the primary species-specific xenosensors that mediate the adaptive hepatic response, and may represent the critical biochemical mechanism of human xenoprotection.
Van Herwaarden et al. (2007) found that mice lacking all 8 functional Cyp3a genes (Cyp3a -/- mice) were viable and fertile and appeared normal. However, these mice exhibited impaired detoxification capacity when exposed to the chemotherapeutic agent docetaxel and showed increased sensitivity to docetaxel toxicity. Expression of human CYP3A4 in intestine of transgenic Cyp3a -/- mice increased docetaxel absorption into the bloodstream, whereas expression of CYP3A4 in liver aided systemic docetaxel clearance. Van Herwaarden et al. (2007) concluded that CYP3A4 has tissue-specific functions in xenobiotic metabolism.
Rebbeck et al. (1998) observed a polymorphism in the nifedipine-specific response element of the CYP3A4 promoter, which they termed CYP3A4-V. Walker et al. (1998) reported that agggcaagag was the most frequent form in Caucasians and Taiwanese; agggcaggag (CYP3A4-V) was present in 9% of whites, 53% of African Americans, and 0% of Taiwanese. A significant deficit of the CYP3A4-V form was found by Felix et al. (1998) in subjects who developed treatment-related leukemia after administration of chemotherapeutic agents that are metabolized by CYP3A.
Paris et al. (1999) found that the CYP3A4-V polymorphism is associated with higher Gleason grade and TNM stage prostate cancer, i.e., more malignant characteristics. The associations were most pronounced among patients older than 65 years of age with no family history (Rebbeck et al., 1998; Paris et al., 1999). Given that the African American population is genetically heterogeneous because of its African ancestry and subsequent admixture with European Americans, case-control studies with African Americans are highly susceptible to spurious associations resulting from population stratification. The frequency of prostate cancer is highest in African Americans, intermediate in non-Hispanic whites, and lowest among Asians (see 176807). To test for association with prostate cancer, Kittles et al. (2002) genotyped CYP3A4-V in 1,376 chromosomes from prostate cancer patients and age- and ethnicity-matched controls representing African Americans, Nigerians, and European Americans. Ten unlinked genetic markers were genotyped to detect population stratification among the African American samples. Sharp differences in CYP3A4-V frequencies were observed between Nigerian and European American controls. An association uncorrected for stratification was observed between CYP3A4-V and prostate cancer in African Americans (P = 0.007). A nominal association was also observed among European Americans (P = 0.02), but not Nigerians. The unlinked genetic marker test provided strong evidence of population stratification among African Americans. Because of the high level of stratification, the corrected P value for association between prostate cancer and CYP3A4-V was not significant.
In 2 unrelated girls (P1.1 and P2.1) with vitamin D-dependent rickets (VDDR3; 619073), Roizen et al. (2018) identified heterozygosity for a c.902T-C transition (c.902T-C, NM_017460.5) in the CYP3A4, resulting in an ile301-to-thr (I301T) substitution at a highly conserved residue. The mutation arose de novo in both patients and was not found in 3,000 control exomes or in public variant databases. Analysis of serum 4,25-dihydroxyvitamin D, the principal product of CYP3A4 metabolism of 25-hydroxyvitamin D, showed that the ratio of 4-beta,25-dihydroxyvitamin D to 25-dihydroxyvitamin D was markedly elevated in both patients. Experiments measuring inactivation of 1,25-dihydroxyvitamin D in a mammalian cell 2-hybrid system showed that the I301T variant is nearly 10-fold more active than wildtype CYP3A4, and nearly twice as active as the principal inactivator of 1,25-dihydroxyvitamin D3, CYP24A1 (126065). However, the I301T mutant did not show increased activity for non-vitamin D substrates.
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