Hormonal regulation of CYP2E1 and CYP2C11 in rat liver and kidney

This research was conducted to investigate the role of hormone(s) in the regulation of microsomal P450 2C11, 2E1 and NADPH-P450 reductase in male Sprague-Dawley rat liver and kidney. The hypotheses were that: (1) GH positively regulates CYP2C11 expression in male rat liver; (2) GH down-regulates the expression of CYP2E1 in male rat liver and GH regulation of hepatic CYP2E1 expression is at the transcription rate of the gene; (3) hormone(s) other than GH are responsible for the down-regulation of CYP2C11 and CYP2E1 in rat kidney; and (4) P450 reductase is differentially regulated in rat liver and kidney.; Hepatic and renal CYP2C11 apoprotein and mRNA levels were measured from rats depleted of hormones by hypophysectomy or anti-rGH serum treatment. GH depletion by either hypophysectomy or anti-rGH serum significantly decreased hepatic CYP2C11 apoprotein and mRNA levels. The loss of CYP2C11 in rat liver by Hx was prevented by GH or rat pituitary extract, but not testosterone replacement. Rat pituitary extract or testosterone, but not GH, prevented the decrease in renal CYP2C11 expression by Hx and the effects of pituitary extract was dependent on the intact testes. Neutralization of rGH by anti-rGH significantly reduced CYP2C11 mRNA level in rat kidney and also reduced serum testosterone in the absence of changes in serum LH concentrations. These results suggest that while hepatic CYP2C11 is regulated by GH, rat renal CYP2C11 is regulated primarily by gonadal steroids.; Renal CYP2E1 apoprotein and mRNA levels from male rat under hormonal manipulation of hypophysectomy and subsequent hormone replacement were measured and these parameters were compared with those of liver. The results demonstrated that renal CYP2E1 expression is under the influence of both GH and gonadal steroid hormones, while hepatic CYP2E1 is primarily under the negative regulation of GH at the CYP2E1 gene transcription rate.; The mechanism(s) underlying the discordance between the drastically increased CYP2E1 apoprotein level and the unaltered or slightly increased CYP2E1-dependent enzyme activity in rat liver and kidney was investigated. The results demonstrated that the discordance can be best explained by decreased P450 reductase activity (rate-limiting factor in P450 system) associated with Hx. These results also suggested the differential regulation of P450 reductase in rat liver and kidney. While rGH appears not to affect hepatic P450 reductase expression, rGH affects renal P450 reductase expression at both apoprotein and mRNA levels.; In order to more definitively identify the role of GH in the regulation of hepatic CYP2E1, a more specific method of GH depletion, anti-rGH serum, was studied. Neutralization of GH by anti-rGH serum significantly decreased hepatic CYP2E1 apoprotein and mRNA levels. These results are contrary to those from Hx model. The possible mechanism(s) for the complex effects observed are discussed.; It is concluded that: (1) GH indeed up-regulates CYP2C11 in adult rat liver; (2) CYP2C11 is expressed in adult male rat kidney and gonadal steroid hormones (probably androgens) up-regulate this expression; (3) GH down-regulates CYP2E1 expression in rat liver by decreasing the gene transcription rate; (4) both GH and gonadal steroid hormones are responsible for the negative regulation of CYP2E1 expression in rat kidney; (5) GH is also partially responsible for the regulation of P450 reductase expression in rat kidneys.