Gene structure of CYP3A4, an adult‐specific form of cytochrome P450 in human livers, and its transcriptional control

Abstract

Biochemistry 29, . The sequences of three genomic clones for CYP3A4 were analyzed for all exons, exon-intron junctions and the 5'-flanking region from the major transcription site to nucleotide position -1105, and compared with those of the CYP3A7 gene, a fetal-specific form of cytochrome P450 in humans. The results showed that the identity of 5'-flanking sequences between CYP3A4 and CYP3A7 genes was 91 %, and that each 5'-flanking region had characteristic sequences termed as NFSE (P450N,-specific element) and HFLaSE (P450HFLa specific element), respectively. A basic transcription element (BTE) also lay in the 5'-flanking region of the CYP3A4 gene as seen in many CYP genes [Yanagida, A., Sogawa, K., Yasumoto, K. & Fujii-Kuriyama, Y. (1990) Mol. Cell. Biol. 10, 1470-14751. The BTE binding factor (BTEB) was present in both adult and fetal human livers.To examine the transcriptional activity of the CYP3A4 gene, DNA fragments in the 5'-flanking region of the gene were inserted in front of the simian virus 40 promoter and the chloramphenicol acetyltransferase structural gene, and the constructs were transfected in HepG2 cells. The analysis of the chloramphenicol acetyltransferase activity indicated that (a) suecific element(s) which could bind with a fa&or(s) in livers was present in the the transcriptional activity.Cytochrome P450 is a heme-containing enzyme which plays central roles in the oxidative and reductive metabolism of a variety of endogenous as well as exogenous compounds. It is generally known that there are numbers of forms of cytochrome P450, which are classified into families according to the homology of their nucleotide sequences 111.Among families of cytochrome P450, the CYP2C and CYP3A families are unique in that there are many forms in each family, and that these enzyme proteins are present in larger amounts in human liver microsomes, compared with other forms of cytochrome P450 121. The CYP3A, CYP3A4 (P450N,.) and CYP3 A7 (P450HFLa) proteins have been purified from human adult and fetal livers, respectively [3-51.Correspondence to T. Kamataki, Division of Drug Metabolism, Faculty of Pharmaceutical Sciences, Hokkaido University, N12W6, Kitaku, Sapporo, Hokkaido, 060 JapanAhhreviations. BTE, basic transcription element ; BTEB, BTE binding factor; CAT, chloramphenicol acetyltransferase; CUP, cytochrome P450; DMEM, Dulbecco's modified Eagles medium; ER, estrogen receptor; ERE, estrogen response element; GR, glucocorticoid receptor; GRE, glucocorticoid response element; HFLaSE, P450HFLa-specific element; HNF-4, hepatic nuclear factor-4 ; HNF-5, hepatic nuclear factor-5 ; NFSE, P450,,-specific element; PR, progesterone receptor; PRE, progesterone response element; SV40, simian virus 40.Enzymes. Cytochrome P450 (EC 1.14.14.1 .); chloramphenicol acetyltransferase (EC 2.3.1.28.).Note. The 5'-flanking sequence data of CYP3A4 gene published here have been deposited with the DDBJ/EMBL/GenBank and are available under the accession number D11131. ~, I5'-flanking region of the CYP3A4 gene to show In addition, f...

Expression of CYP3A in the Human Liver — Evidence that the Shift between CYP3A7 and CYP3A4 Occurs Immediately After Birth

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Apparent Low Frequency of Sequence Variability within the Proximal Promoter Region of the Cytochrome P450 (CYP) 3A5 Gene in Established Cell Lines from Japanese Individuals.

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Unique CYP3A4 genetic variant in Brazilian tuberculosis patients with/without HIV

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