Molecular mechanisms of polymorphic CYP3A7 expression in adult human liver and intestine.
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 CYP3A genes to total CYP3A activity remain unclear. To elucidate the role of CYP3A7, 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, the CYP3A7*1C allele contains the proximal ER6 motif of CYP3A4. 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 in CYP3A7*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 CYP3A4 mediates the high expression of CYP3A7 in subjects carrying CYP3A7*1C.
Burk
Oliver
O
Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Auerbachstrasse 112, D-70376 Stuttgart, Germany. oliver.burk@ikp-stuttgart.de
Tegude
Heike
H
Koch
Ina
I
Hustert
Elisabeth
E
Wolbold
Renzo
R
Glaeser
Hartmut
H
Klein
Kathrin
K
Fromm
Martin F
MF
Nuessler
Andreas K
AK
Neuhaus
Peter
P
Zanger
Ulrich M
UM
Eichelbaum
Michel
M
Wojnowski
Leszek
L
D000328:Adult; D000483:Alleles; D001189:Aryl Hydrocarbon Hydroxylases; D001483:Base Sequence; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D017931:DNA Primers; D004386:Duodenum / Q000201:enzymology; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007421:Intestine, Small / Q000201:enzymology*; D008099:Liver / Q000201:enzymology*; D016296:Mutagenesis; D011110:Polymorphism, Genetic; D012150:Polymorphism, Restriction Fragment Length; D011401:Promoter Regions, Genetic; D014158:Transcription, Genetic
D017931:DNA Primers; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C103123:CYP3A7 protein, human; D051544:Cytochrome P-450 CYP3A