Restoration of cytochrome P450 2C11 in vitamin A‐deficient rat liver by exogenous androgen

Abstract

Down-regulation of microsomal androgen-dependent CYP2C11 is produced in male rat liver by dietary vitamin A deficiency. Decreased circulating androgen concentrations also occur in vitamin A-deficient male rats. Both effects are prevented by addition of all-trans-retinoic acid to the diet. The present study evaluated directly whether androgen deficiency may be responsible for the down-regulation of 2C11 in vitamin A-deficient male rats. The major finding was that subcutaneous administration of the androgen methyltrienolone (MT) during the final week of the study restored CYP2C11 protein and its associated steroid 16alpha-hydroxylation activities to control levels; CYP2C11 mRNA was also restored. Despite the efficient restoration of CYP2C11 at a pretranslational level, no alteration in vitamin A status was apparent and animals remained vitamin A deficient after MT treatment. The possibility was assessed that vitamin A can maintain the microsomal content of CYP2C11 in normal liver. However, in contrast to MT, administration of ATRA to gonadectomized male rats did not restore 2C11 in liver. These findings establish that the major effect of vitamin A deficiency on CYP2C11 in male rat liver is mediated indirectly by androgen deficiency.

Differential regulation of endobiotic‐oxidizing cytochromes P450 in vitamin A‐deficient male rat liver

“…In one experiment animals received the deficient diet that was supplemented with 12 μg ATRA g −1 (Martini et al ., 1995) for a further 7 days. In another study MT was administered to vitamin A‐deficient rats at a dose of 0.625 mgkg −1 in propylene glycol by subcutaneous injection once daily for 5 days; treatment controls received solvent alone (Murray et al ., 1996). In a further experiment vitamin A‐deficient rats were administered recombinant human growth hormone (hGH; Aza Research, West Ryde, NSW, Australia) in saline at a dose of 12.5 μg 100 g −1 body weight by subcutaneous injection at 12 h intervals for 7 days (Waxman et al ., 1991), during which animals were allowed free access to water and the appropriate diet.…”

“…Replacement of dietary vitamin A esters with all‐ trans ‐retinoic acid (ATRA) prevented the loss of hepatic CYP2C11 expression and circulating androgen produced by vitamin A‐deficiency (Martini et al ., 1995). Subsequently, administration of androgen to vitamin A‐deficient male rats was found to restore hepatic CYP2C11 expression and function (Murray et al ., 1996).…”

Altered CYP Expression and Function in Response to Dietary Factors: Potential Roles in Disease Pathogenesis

“…Dietary supplementation with all-trans-retinoic acid (ATRA), a biologically active form of the vitamin that is usually absent from the diet, prevented the down-regulation of CYP2C11 and the decline in circulating androgen levels that occurred in vitamin A-deficient animals [53]. Moreover, androgen administration to vitamin A-deficient male rats restored CYP2C11 without influencing vitamin A status [54], which is consistent with the role of androgen in expression of this CYP in male rat liver [55,56] (Fig. 5).…”

Steroid binding sites in liver membranes: Interplay between glucocorticoids, sex steroids, and pituitary hormones

“…The relatively slow increase in the re-expression of the LAGS in response to retinol acetate treatment suggests that the LAGS may not be directly dependent on or solely dependent on retinoids for expression. Similarly to LAGS, CYP2C11 expression is lost in vitamin A-deficient rats [44]. However, the loss of CYP2C11 expression in vitamin A-deficient male rats has been shown to be due indirectly to androgen deficiency since androgen treatment restores CYP2C11 expression in vitamin A-deficient rats [44].…”

“…Similarly to LAGS, CYP2C11 expression is lost in vitamin A-deficient rats [44]. However, the loss of CYP2C11 expression in vitamin A-deficient male rats has been shown to be due indirectly to androgen deficiency since androgen treatment restores CYP2C11 expression in vitamin A-deficient rats [44]. In contrast, the LAGS expression is unaffected by androgen levels as determined by orchiectomy [7,32].…”