The Journal of Biochemistry
Online ISSN : 1756-2651
Print ISSN : 0021-924X
Genetic Polymorphisms in the 5'-Flanking Region Change Transcriptional Regulation of the Human Cytochrome P45011E1 Gene
Shin-ichi HayashiJunko WatanabeKaname Kawajiri
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1991 Volume 110 Issue 4 Pages 559-565

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Abstract

We identified genetic polymorphisms in the 5'-flanking region of the human cytochrome P45011E1 gene and investigated the effect of these polymorphisms on the transcriptional regulation of the gene. PCR direct sequencing of the two homozygous alleles [types A (c1/c1) and C (c2/c2)] revealed the existence of several point mutations in the distal 5'-flanking region of the gene, but no differences in the proximal promoter region. The DNA segment ( -1372 to -960) placed upstream of SV40 promoter and the chloramphenicol acetyltrans-ferase (CAT) gene enhanced the expression of the gene, and the enhancement of expression by type C DNA was about 10 times that by its type A counterpart. DNase I footprinting analysis showed at least one protected region in which one of the polymorphic loci (RsaI polymorphism) was located. The DNase I sensitivities and protection profiles of the two genotypes were different. The protected region had high homology to the consensus sequence of the binding region of liver specific transcription factor HNF1 (LF-B1), and this was confirmed by gel retardation assay. These results indicate that genetic polymorphisms in the 5'-flanking region of the human P45011E1 gene affect its binding of trans-acting factor and change its transcriptional regulation. This may lead to inter-individual differences of microsomal drug oxidation activity.

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© The Japanese Biochemical Society
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