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Molecular Mechanisms of Polymorphic CYP3A7 Expression in Adult Human Liver and Intestine*

Open AccessPublished:April 08, 2002DOI:https://doi.org/10.1074/jbc.M202345200
      Human CYP3A enzymes play a pivotal role in the metabolism of many drugs, and the variability of their expression among individuals may have a strong impact on the efficacy of drug treatment. However, the individual contributions of the four CYP3Agenes to total CYP3A activity remain unclear. To elucidate the role ofCYP3A7, we have studied its expression in human liver and intestine. In both organs, expression of CYP3A7 mRNA was polymorphic. The recently identified CYP3A7*1C allele was a consistent marker of increased CYP3A7 expression both in liver and intestine, whereas the CYP3A7*1B allele was associated with increased CYP3A7 expression only in liver. Because of the replacement of part of the CYP3A7 promoter by the corresponding region of CYP3A4, theCYP3A7*1C allele contains the proximal ER6 motif ofCYP3A4. The pregnane X and constitutively activated receptors were shown to bind with higher affinity to CYP3A4-ER6 than to CYP3A7-ER6 motifs and transactivated only promoter constructs containing CYP3A4-ER6. Furthermore, we identified mutations inCYP3A7*1C in addition to the ER6 motif that were necessary only for activation by the constitutively activated receptor. We conclude that the presence of the ER6 motif of CYP3A4mediates the high expression of CYP3A7 in subjects carryingCYP3A7*1C.
      PXR
      pregnane X receptor
      CAR
      constitutively activated receptor
      RXR
      retinoic X receptor
      HNF
      hepatocyte nuclear factor
      Cytochrome P450 enzymes play a pivotal role in the oxidative, peroxidative, and reductive metabolism of many endogenous compounds, procarcinogens, and drugs. The CYP3A subfamily composed of CYP3A4, CYP3A5, CYP3A7, and CYP3A43 in humans is of special importance because it accounts for as much as 30% of total liver cytochrome P450 content (
      • Shimada T.
      • Yamazaki H.
      • Mimura M.
      • Inui Y.
      • Guengerich F.P.
      ). At least 50% of all medicines are metabolized by enzymes of the CYP3A subfamily (
      • Guengerich F.P.
      ). The most abundant CYP3A isoform in liver and intestine is CYP3A4. Its interindividual hepatic expression varies 60-fold (
      • Özdemir V.
      • Kalow W.
      • Tang B.-K.
      • Paterson A.D.
      • Walker S.E.
      • Endrenyi L.
      • Kashuba A.D.
      ), and the in vivo function as assessed by clearance displays at least a 20-fold difference (
      • Wilkinson G.R.
      ). Induction by xenobiotics (e.g. rifampin) and endogenous compounds (e.g. steroid hormones) further modulates the variability of CYP3A4 expression among individuals. The induction of CYP3A4and most likely that of other CYP3A genes is mediated by the nuclear receptor NR1I2 (pregnane X receptor (PXR)1) (reviewed in Ref.
      • Moore J.T.
      • Kliewer S.A.
      ).CYP3A4-inducing compounds bind to PXR and stimulate the transcriptional activity of the receptor. Additional nuclear receptors such as NR1I3 (constitutively activated receptor (CAR)) and NR1I1 (vitamin D receptor) have also been implicated in the transcriptional regulation of CYP3A4 (
      • Zelko I.
      • Negishi M.
      ,
      • Thummel K.E.
      • Brimer C.
      • Yasuda K.
      • Thottassery J.
      • Senn T.
      • Lin Y.
      • Ishizuka H.
      • Kharasch E.
      • Schuetz J.
      • Schuetz E.
      ). Although the substrate specificity of CYP3A5 is similar to that of CYP3A4, CYP3A5 has been regarded to be less important for drug elimination because it is expressed at much lower levels than CYP3A4 in most livers of Caucasian origin (
      • Hustert E.
      • Haberl M.
      • Burk O.
      • Wolbold R., He, Y.-Q.
      • Klein K.
      • Nuessler A.C.
      • Neuhaus P.
      • Klattig J.
      • Eiselt R.
      • Koch I.
      • Zibat A.
      • Brockmöller J.
      • Halpert J.R.
      • Zanger U.M.
      • Wojnowski L.
      ). CYP3A43 is expressed at very low levels in adult human livers, accounting for only 0.1–0.2% of CYP3A4transcripts (
      • Gellner K.
      • Eiselt R.
      • Hustert E.
      • Arnold H.
      • Koch I.
      • Haberl M.
      • Deglmann C.J.
      • Burk O.
      • Buntefuss D.
      • Escher S.
      • Bishop C.
      • Koebe H.-G.
      • Brinkmann U.
      • Klenk H.-P.
      • Kleine K.
      • Meyer U.A.
      • Wojnowski L.
      ,
      • Westlind A.
      • Malmebo S.
      • Johansson I.
      • Otter C.
      • Andersson T.B.
      • Ingelman-Sundberg M.
      • Oscarson M.
      ). Therefore, its contribution to the elimination of CYP3A substrates is regarded to be negligible (
      • Westlind A.
      • Malmebo S.
      • Johansson I.
      • Otter C.
      • Andersson T.B.
      • Ingelman-Sundberg M.
      • Oscarson M.
      ). This variability in CYP3A expression and function explains why the intensity and duration of drug action and the occurrence of side effects show large patient-to-patient variability. Although a recent analysis suggests that, depending on the drug, 60–90% of patient-to-patient variability in CYP3A function is caused by genetic factors (
      • Özdemir V.
      • Kalow W.
      • Tang B.-K.
      • Paterson A.D.
      • Walker S.E.
      • Endrenyi L.
      • Kashuba A.D.
      ), the sources for variability in constitutive CYP3A expression remain largely unknown. However, a common genetic polymorphism in intron 3 ofCYP3A5 was recently identified. It results in high expression genotypes and explains the >10-fold increase in CYP3A5 protein expression observed in 10–30% of livers of Caucasian origin (
      • Hustert E.
      • Haberl M.
      • Burk O.
      • Wolbold R., He, Y.-Q.
      • Klein K.
      • Nuessler A.C.
      • Neuhaus P.
      • Klattig J.
      • Eiselt R.
      • Koch I.
      • Zibat A.
      • Brockmöller J.
      • Halpert J.R.
      • Zanger U.M.
      • Wojnowski L.
      ,
      • Kuehl P.
      • Zhang J.
      • Lin Y.
      • Lamba J.
      • Assem M.
      • Schuetz J.
      • Watkins P.B.
      • Daly A.
      • Wrighton S.A.
      • Hall S.D.
      • Maurel P.
      • Relling M.
      • Brimer C.
      • Yasuda K.
      • Venkataramanan R.
      • Strom S.
      • Thummel K.
      • Boguski M.S.
      • Schuetz E.
      ). In some persons, CYP3A5 can contribute to >50% of total CYP3A content, thus exceeding CYP3A4 levels. Correspondingly, CYP3A5 has been proposed to contribute substantially to the elimination of CYP3A substrates (
      • Kuehl P.
      • Zhang J.
      • Lin Y.
      • Lamba J.
      • Assem M.
      • Schuetz J.
      • Watkins P.B.
      • Daly A.
      • Wrighton S.A.
      • Hall S.D.
      • Maurel P.
      • Relling M.
      • Brimer C.
      • Yasuda K.
      • Venkataramanan R.
      • Strom S.
      • Thummel K.
      • Boguski M.S.
      • Schuetz E.
      ). These findings could explain why there is less variability in the in vivo clearance than one would predict based on the >60-fold variability in CYP3A4 expression.
      The role of CYP3A7 in the biotransformation of CYP3A substrates in adult liver and intestine is not known. CYP3A7 accounts for 30–50% of total cytochrome P450 in fetal liver (
      • Shimada T.
      • Yamazaki H.
      • Mimura M.
      • Wakamiya N.
      • Ueng Y.F.
      • Guengerich F.P.
      • Inui Y.
      ) and was at first regarded to be exclusively expressed there (
      • Komori M.
      • Nishio K.
      • Kitada M.
      • Shiramatsu K.
      • Muroya K.
      • Soma M.
      • Nagashima K.
      • Kamataki T.
      ). Since then, CYP3A7expression was detected in 54–88% of adult livers (
      • Schuetz J.D.
      • Beach D.L.
      • Guzelian P.S.
      ,
      • Greuet J.
      • Pichard L.
      • Bonfils C.
      • Domergue J.
      • Maurel P.
      ). However, quantitative data on CYP3A7 expression in adult livers are missing. Moreover, the mechanisms responsible for expression ofCYP3A7 in adult livers remain unknown.
      Using a large collection of human livers, we report here thatCYP3A7 mRNA is polymorphically expressed in both liver and intestine, with ∼11% of subjects belonging to a distinct subgroup of high expression phenotype. Two-thirds of the subjects in this group carry the CYP3A7*1C or (less frequently) theCYP3A7*1B promoter allele. The CYP3A7*1C allele is the exclusive marker of high CYP3A7 expression in the intestine. Functional differences between CYP3A7 andCYP3A7*1C proximal promoter ER6 (evertedrepeat separated by 6 base pairs) motifs in binding and activation by the nuclear receptors PXR and CAR were identified as the mechanisms responsible for the high CYP3A7expression in CYP3A7*1C carriers.

      DISCUSSION

      In this study, we have described the polymorphic expression ofCYP3A7 in adult human liver and intestine and analyzed the functional consequences of two promoter alleles for the expression of the gene. CYP3A7 mRNA was found in all livers, but showed pronounced interindividual variability. There was a non-gaussian distribution, with 11% of livers expressing >25,000 transcripts/ng of total RNA. Because at the present time no CYP3A7-specific antibody is available, expression at the protein level could not be studied. Nearly two-thirds of the subjects in the subgroup with hepatic expression of >25,000 transcripts of CYP3A7 mRNA/ng of total RNA carried the CYP3A7*1C allele or, less frequently, theCYP3A7*1B allele. The mechanism of the increasedCYP3A7 expression in the subjects without these alleles remains to be elucidated, but it could involve additional genetic markers or induction by xenobiotics. Only one subject in this group had been treated with nifedipine, which is a known inducer ofCYP3A4 expression in vitro (
      • Drocourt L.
      • Pascussi J.-M.
      • Assenat E.
      • Fabre J.-M.
      • Maurel P.
      • Vilarem M.-J.
      ). However, the expression of CYP3A4 in the corresponding liver was low (data not shown). Thus, it is very likely that the high expression ofCYP3A7 in subjects without the CYP3A7*1C orCYP3A7*1B allele is caused by yet unknown genetic variants rather than by induction, but this remains to be verified experimentally. Induction can be ruled out as the mechanism of highCYP3A7 expression in the subjects carryingCYP3A7*1C or CYP3A7*1B because none of these patients was treated with known CYP3A inducers.
      The increased CYP3A7 expression observed in ∼11% of adult human livers could have consequences for drug biotransformation. For a number of drugs, data on substrate affinity and specificity using cDNA-expressed CYP3A4, CYP3A5, and CYP3A7 demonstrate similarity (
      • Gillam E.M.
      • Wunsch R.M.
      • Ueng Y.F.
      • Shimada T.
      • Reilly P.E.
      • Kamataki T.
      • Guengerich F.P.
      ). On the other hand, there are also examples of pronounced differences in substrate affinity among CYP3A isoforms, including CYP3A7 (
      • Marill J.
      • Cresteil T.
      • Lanotte M.
      • Chabot G.G.
      ,
      • Ohmori S.
      • Nakasa H.
      • Asanome K.
      • Kurose Y.
      • Ishii I.
      • Hosokawa M.
      • Kitada M.
      ). For example, CYP3A7 metabolizes retinoic acid 25 times more efficiently than CYP3A4 (
      • Marill J.
      • Cresteil T.
      • Lanotte M.
      • Chabot G.G.
      ). Based on the expression levels of CYP3A7 in the subjects of the high expression subgroup, which come up to 20% of the combinedCYP3A4 and CYP3A7 pool, CYP3A7 could contribute to up to 80% of total biotransformation of retinoic acid. Thus, the polymorphic expression of CYP3A7 in adult human livers could be responsible for part of the variability of CYP3A activity among individuals.
      In contrast to previous studies that did not detect CYP3A7expression in fetal and adult human intestine (
      • Yang H.-Y.
      • Lee Q.P.
      • Rettie A.E.
      • Juchau M.R.
      ,
      • Kolars J.C.
      • Schmiedlin-Ren P.
      • Schuetz J.D.
      • Fang C.
      • Watkins P.B.
      ,
      • Kivistö K.T.
      • Bookjans G.
      • Fromm M.F.
      • Griese E.-U.
      • Münzel P.
      • Kroemer H.K.
      ), we demonstratedCYP3A7 expression in every intestine sample investigated. This is in all probability due to the more sensitive method used. However, high amounts of CYP3A7 transcripts were present only in intestine samples of subjects with the CYP3A7*1Callele. This observation demonstrates differences in the regulation ofCYP3A7 between liver and intestine. In addition to theCYP3A7*1C-dependent regulation, further mechanisms responsible for high CYP3A7 expression (such asCYP3A7*1B-dependent regulation) obviously exist in liver. However, half of the subjects from whom we obtained intestine samples, including the CYP3A7*1C andCYP3A7*1B heterozygotes, were treated with known inducers ofCYP3A4 (omeprazole, nifedipine, reserpine, or St. John's wort). Because the CYP3A7*1C heterozygotes showed only low intestinal CYP3A4 expression, it is unlikely that their high intestinal CYP3A7 expression was caused by induction. This assumption is further supported by a lack of association between treatment with inducers and CYP3A7 expression (data not shown) and the tissue-specific effects of the two alleles determiningCYP3A7 expression. In addition, reserpine, which was administered to one CYP3A7*1C heterozygote, did not induceCYP3A7 expression in an intestinal cell line, whereasCYP3A4 was induced by reserpine in the same cell line (
      • Schuetz E.G.
      • Beck W.T.
      • Schuetz J.D.
      ).
      Furthermore, we have provided a mechanistic explanation for the increased expression of CYP3A7 in the individuals carrying the more frequent marker of the CYP3A7 polymorphism, theCYP3A7*1C allele. The CYP3A7*1C mutation has arisen through replacement of part of the CYP3A7 promoter by the corresponding region of CYP3A4. This led to the substitution of CYP3A7-ER6 for CYP3A4-ER6. The ER6 motif in the proximal promoter of the CYP3A4 gene is one of the two elements mediating PXR-dependent activation. The second element is the distal xenobiotic-responsive enhancer module (
      • Goodwin B.
      • Hodgson E.
      • Liddle C.
      ). Two bases are different between the proximal ER6 motifs ofCYP3A4 and CYP3A7 (
      • Pascussi J.-M.
      • Jounaidi Y.
      • Drocourt L.
      • Domergue J.
      • Balabaud C.
      • Maurel P.
      • Vilarem M.-J.
      ). We showed that the presence of CYP3A4-ER6 was responsible for the high expression ofCYP3A7 in carriers of the CYP3A7*1C allele. PXR exhibited stronger binding to CYP3A4-ER6 than to CYP3A7-ER6. However, in contrast to the results presented by Pascussi et al.(
      • Pascussi J.-M.
      • Jounaidi Y.
      • Drocourt L.
      • Domergue J.
      • Balabaud C.
      • Maurel P.
      • Vilarem M.-J.
      ), this differential binding also resulted in a dramatic difference in the PXR-mediated transactivation of CYP3A4 andCYP3A7 promoters. The discrepancy is most likely due to differences between the natural CYP3A7 promoter used in our study and the reporter gene containing multimerized CYP3A7-ER6 motifs used by Pascussi et al. (
      • Pascussi J.-M.
      • Jounaidi Y.
      • Drocourt L.
      • Domergue J.
      • Balabaud C.
      • Maurel P.
      • Vilarem M.-J.
      ). Our data clearly demonstrate that the proximal ER6 motifs of CYP3A4 and CYP3A7are functionally different with respect to binding and activation by PXR. This difference appears to be the mechanism of theCYP3A7*1C effect on CYP3A7 expression.
      PXR is not the only transcription factor binding to the proximal ER6 motif of CYP3A4 and activating its transcription. Recently, it has been shown that CAR and vitamin D receptor, which belong to the same subfamily of nuclear receptors (NR1I) as PXR, also regulateCYP3A4 expression (
      • Zelko I.
      • Negishi M.
      ,
      • Thummel K.E.
      • Brimer C.
      • Yasuda K.
      • Thottassery J.
      • Senn T.
      • Lin Y.
      • Ishizuka H.
      • Kharasch E.
      • Schuetz J.
      • Schuetz E.
      ,
      • Xie W.
      • Barwick J.L.
      • Simon C.M.
      • Pierce A.M.
      • Safe S.
      • Blumberg B.
      • Guzelian P.S.
      • Evans R.M.
      ). Similarly to PXR, CAR showed stronger binding to CYP3A4-ER6 than to CYP3A7-ER6 and activatedCYP3A4 and CYP3A7*1C promoters. But in contrast to PXR, the presence of CYP3A4-ER6, although necessary, was not sufficient for CAR activation. Additional single base mutations of theCYP3A7*1C allele proved to be necessary. We identified position –188 as the most crucial one, but also positions –181, −179, and –178 were involved in the activation by CAR. The –188G>T mutation in CYP3A7*1C creates a putative HNF-3-binding site, whereas mutations of positions –181, −179, and −178 are not located within any of the known transcription factor-binding sites (
      • Hashimoto H.
      • Toide K.
      • Kitamura R.
      • Fujita M.
      • Tagawa S.
      • Itoh S.
      • Kamataki T.
      ). The –129A>C mutation inCYP3A7*1C destroys a functional HNF-3-binding site of theCYP3A7 promoter (
      • Saito T.
      • Takahashi Y.
      • Hashimoto H.
      • Kamataki T.
      ) and creates a putative octamer motif (
      • Hashimoto H.
      • Toide K.
      • Kitamura R.
      • Fujita M.
      • Tagawa S.
      • Itoh S.
      • Kamataki T.
      ). The strong dependence of CAR-mediated activation on position –188 and, to a more limited extent, on at least one of positions –181, −179, and −178 probably reflects functional interactions between CAR and other transcription factors binding to these sequences. The nature of these interactions and the role of HNF-3 have to be elucidated in future studies.
      The involvement of PXR in the induction of CYP3A genes is established, but data on its role in the regulation of constitutiveCYP3A expression are less convincing. A targeted deletion of PXR did not alter the constitutive expression of CYP3A in one strain of mice (
      • Xie W.
      • Barwick J.L.
      • Downes M.
      • Blumberg B.
      • Simon C.M.
      • Nelson M.C.
      • Neuschwander-Tetri B.A.
      • Brunt E.M.
      • Guzelian P.S.
      • Evans R.M.
      ), whereas it resulted in a 3-fold reduction ofCYP3A expression in another mouse strain (
      • Kast H.R.
      • Goodwin B.
      • Tarr P.T.
      • Jones S.A.
      • Anisfeld A.A.
      • Stoltz C.M.
      • Tontonoz P.
      • Kliewer S.
      • Willson T.M.
      • Edwards P.A.
      ). The data presented in our study support the hypothesis that nuclear receptors binding to the proximal ER6 motif may play a role in the constitutive expression of CYP3A. The describedCYP3A7*1C-dependent mechanism of highCYP3A7 expression is based on functional differences between the proximal ER6 motifs of CYP3A4 and CYP3A7. The proximal ER6 motif of CYP3A4, but not that ofCYP3A7, mediates activation by the nuclear receptors PXR and CAR. Therefore, the induction of CYP3A7 observed in most, although not all, primary adult hepatocyte cultures and hepatoma cell lines after treatment with the PXR ligands rifampin, clotrimazole, and RU486 (
      • Greuet J.
      • Pichard L.
      • Bonfils C.
      • Domergue J.
      • Maurel P.
      ,
      • Pascussi J.-M.
      • Jounaidi Y.
      • Drocourt L.
      • Domergue J.
      • Balabaud C.
      • Maurel P.
      • Vilarem M.-J.
      ) could be mediated by the recently described xenobiotic-responsive enhancer module in the CYP3A7 far upstream regulatory region that is functionally conserved betweenCYP3A4 and CYP3A7 (
      • Bertilsson G.
      • Berkenstam A.
      • Blomquist P.
      ).
      No clues regarding the mechanism of action of theCYP3A7*1B allele can be derived from the sequence context of the single nucleotide polymorphism that constitutes the allele. The mechanism has to be clarified in future functional studies.
      In conclusion, this study provides clear evidence for an association of the CYP3A7*1B and/or CYP3A7*1C allele with high expression of CYP3A7 in adult liver and intestine. These alleles could serve as markers for the variable CYP3A activity. Furthermore, we identified functional differences between the ER6 motifs of CYP3A4 and CYP3A7 proximal promoters in binding and activation by the nuclear receptors PXR and CAR. Taken together, these results provide a mechanistic explanation for the increased CYP3A7 expression in CYP3A7*1Ccarriers. Whether the proximal ER6 motif and these nuclear receptors participate also in the developmental switch from CYP3A7 toCYP3A4 expression in liver, occurring immediately after birth (
      • Lacroix D.
      • Sonnier M.
      • Moncion A.
      • Cheron G.
      • Cresteil T.
      ), remains to be elucidated in future studies.

      Note Added in Proof

      The high prevalence of CYP3A7*1C alleles in subjects expressing high levels of CYP3A7 transcripts is in agreement with expression data presented together with the original description of this allele (
      • Kuehl P.
      • Zhang J.
      • Lin Y.
      • Lamba J.
      • Assem M.
      • Schuetz J.
      • Watkins P.B.
      • Daly A.
      • Wrighton S.A.
      • Hall S.D.
      • Maurel P.
      • Relling M.
      • Brimer C.
      • Yasuda K.
      • Venkataramanan R.
      • Strom S.
      • Thummel K.
      • Boguski M.S.
      • Schuetz E.
      ).

      Acknowledgments

      We are indebted to K. Abuazi de Paulus, R. Weil, and J. Klattig for excellent technical assistance and to P. Fritz for the histological examination of the intestine samples. K. P. Thon (Department of Surgery, Robert Bosch Hospital) and F. Läpple kindly helped to collect the intestine samples. We thank R. Schüle, T. Kamataki (Hokkaido University, Sapporo, Japan), F. J. Gonzales (NCI, Bethesda, MD), and P. Beaune (University René Descartes, Paris, France) for kindly providing plasmids containing human RXRα, CYP3A7,CYP3A4, and CYP3A5 cDNAs, respectively.

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