Effects of Hypoxia-inducible Factor-1α Chemical Stabilizer, CoCl₂ and Hypoxia on Gene Expression of CYP3As in Human Fetal Liver Cells

Abstract

  Distinctive response patterns of CYP3A4 and CYP3A7 to cobalt chloride (CoCl₂) in human fetal liver (HFL) cells were observed and compared with those under hypoxic conditions. The expression levels of CYP3A4 and CYP3A7 mRNAs were decreased by CoCl₂ and hypoxia, although significance could not be determined in HFL cells cultured under 3% O₂. The hypoxia-inducible factor-1α (HIF-1α) protein content in HFL cells was significantly increased by CoCl₂ and 3% O₂. Transcriptional activities of CYP3A4 and CYP3A7 were not altered by 3% O₂ when reporter plasmids containing the promoter region ranging up to about 10 kb and 12 kb upstream, respectively, were transfected into HFL cells, although the activity was significantly suppressed by CoCl₂. These results suggested that the mechanisms controlling CYP3A gene expression of HIF-1α chemical stabilizer in fetal hepatocytes might be different from those in adult hepatocytes, and that HIF-1α is not directly involved in regulation of CYP3A4 or CYP3A7 expression.