Developmental Pharmacogenetics of Liver Microsomal Testosterone Hydroxylases

Negishi, M.

Abstract

This project is aimed at understanding the molecular mechanism(s) of sex-dependent gene regulation of steroid hydroxylases in liver and renal microsomes from mice. Genetic regulation: We defined two loci (Rip and Rsh) which regulate female-specific expression of """"""""I""""""""-P-450, 16Alpha (an isozyme of testosterone 16Alpha-hydroxylase) in liver microsomes and expression of P-450, 15Alpha (an isozyme of testosterone 15Alpha-hydroxylase) in renal microsomes, respectively. With inbred strain (9XA), the Rip locus was located on mouse chromosome 7. The two loci are expected to be transacting genetic elements whose gene products are not yet identified. Hormonal regulation: Growth hormone (GH) is a masculinizing factor which acts by expressing the male-specific isozyme of testosterone 16Alpha-hydroxylase (""""""""C""""""""-P-450, 16Alpha) and representing female-specific hydroxylases (""""""""I""""""""-P-450, 16Alpha and P-459, 15Alpha) in male liver. Estrogen is another repressor of """"""""I""""""""-P-450, 16Alpha in male liver and estrogen-dependent repression is under control of either the Rip locus or a locus closely linked to the Rip locus. Expression of P-450, 15Alpha is growth hormone- and androgen-dependent in mouse kidney. It was also found that the induction of """"""""I""""""""-P-450, 16Alpha by phenobarbital in 129/J mice is due to a derepression, presumably through an interaction with pathway of the hormonal repression of this gene. Cloning and characterization of cDNAs and genomic DNAs: Four different cDNAs for the """"""""I""""""""-P-450, 16Alpha family were isolated and DNA sequence data revealed that three of these cDNAs represent """"""""I""""""""-P-450, 16Alpha mRNAs derived from a single gene by an alternative splicing and utilization of poly A sites. One other cDNA shared 90% DNA sequence homology with """"""""I""""""""-P-450, 16Alpha, 1481bp of """"""""C""""""""-P-450, 16Alpha cDNA were sequenced and the amino acid sequence was deduced from it. """"""""C""""""""-P-450, 16Alpha had only 20% sequence homology with other known P-450s. The """"""""C""""""""-P-450, 16Alpha gene family is on mouse chromosome 15. Two closely related P-450, 15Alpha cDNAs were sequenced (98% homology) and two tandomly repeated P-450, 15Alpha genes were found on mouse chromosome 7.

Funding Agency

• Agency: National Institute of Health (NIH)
• Institute: National Institute of Environmental Health Sciences (NIEHS)
• Type: Intramural Research (Z01)
• Project #: 1Z01ES080040-03
• Application #: 3965317
• Support Year: 3
• Fiscal Year: 1986

Institution

• Name: U.S. National Inst of Environ Hlth Scis
• Country: United States

Publications

Konno, Yoshihiro; Kodama, Susumu; Moore, Rick et al. (2009) Nuclear xenobiotic receptor pregnane X receptor locks corepressor silencing mediator for retinoid and thyroid hormone receptors (SMRT) onto the CYP24A1 promoter to attenuate vitamin D3 activation. Mol Pharmacol 75:265-71

Adair, Jennifer E; Stober, Vandy; Sobhany, Mack et al. (2009) Inter-alpha-trypsin inhibitor promotes bronchial epithelial repair after injury through vitronectin binding. J Biol Chem 284:16922-30

Tien, Eric S; Matsui, Kenji; Moore, Rick et al. (2007) The nuclear receptor constitutively active/androstane receptor regulates type 1 deiodinase and thyroid hormone activity in the regenerating mouse liver. J Pharmacol Exp Ther 320:307-13

Koike, Chika; Moore, Rick; Negishi, Masahiko (2007) Extracellular signal-regulated kinase is an endogenous signal retaining the nuclear constitutive active/androstane receptor (CAR) in the cytoplasm of mouse primary hepatocytes. Mol Pharmacol 71:1217-21

Timsit, Yoav E; Negishi, Masahiko (2007) CAR and PXR: the xenobiotic-sensing receptors. Steroids 72:231-46

Nakamura, Kouichi; Moore, Rick; Negishi, Masahiko et al. (2007) Nuclear pregnane X receptor cross-talk with FoxA2 to mediate drug-induced regulation of lipid metabolism in fasting mouse liver. J Biol Chem 282:9768-76

Yamazaki, Yuichi; Kakizaki, Satoru; Horiguchi, Norio et al. (2007) The role of the nuclear receptor constitutive androstane receptor in the pathogenesis of non-alcoholic steatohepatitis. Gut 56:565-74

Phillips, Jennifer M; Yamamoto, Yukio; Negishi, Masahiko et al. (2007) Orphan nuclear receptor constitutive active/androstane receptor-mediated alterations in DNA methylation during phenobarbital promotion of liver tumorigenesis. Toxicol Sci 96:72-82

Sobhany, Mack; Negishi, Masahiko (2006) Characterization of specific donor binding to alpha1,4-N-acetylhexosaminyltransferase EXTL2 using isothermal titration calorimetry. Methods Enzymol 416:3-12

Inoue, Kaoru; Borchers, Christoph H; Negishi, Masahiko (2006) Cohesin protein SMC1 represses the nuclear receptor CAR-mediated synergistic activation of a human P450 gene by xenobiotics. Biochem J 398:125-33