Induction of cytochrome P450III and P450IV family proteins in streptozotocin-induced diabetes

Abstract

The effect of insulin-dependent diabetes on the hepatic microsomal activity of cytochrome P450III and P450IV family proteins was investigated in rats pretreated with streptozotocin. In order to discern between the effects of the diabetogen per se and those of the ensuing diabetes, streptozotocin-treated rats received in addition either nicotinamide to prevent the onset of diabetes or daily treatment with insulin to antagonize the effects of diabetes. Streptozotocin-treated rats displayed higher ethylmorphine and erythromycin N-demethylase activities and lauric acid hydroxylase activity. Increases were also detected immunologically by using monospecific polyclonal antibodies against the P450III and P450IV families. All effects were prevented by nicotinamide and effectively antagonized by insulin. In order to evaluate the role of the ketone bodies in the diabetes-induced increases in the above activities, rats were rendered hyperketonaemic by dietary administration of medium-chain triacylglycerols. These hyperketonaemic animals displayed high laurate hydroxylase activity and P450IV apoprotein levels, similar to those seen in the diabetic animals. Hyperketonaemia induced by dietary means caused a modest increase in the demethylation of erythromycin and had no significant effect on the N-demethylation of ethylmorphine. Furthermore, no marked increases were evident in the P450III apoprotein levels in the hyperketonaemic animals. It is concluded that insulin-dependent diabetes induces proteins of the P450III and P450IV families, and that the hyperketonaemia that accompanies diabetes is largely responsible for the changes in the latter family.

CYP2E1 and CYP4A as microsomal catalysts of lipid peroxides in murine nonalcoholic steatohepatitis

“…Moreover, CYP4A genes are coregulated with other genes that encode proteins involved in fatty acid β-oxidation (e.g., acetyl CoA oxidase and ketothiolase) and transport (liver fatty acid-binding protein and acyl-CoA-binding protein). It is therefore clear that CYP4A proteins are key intermediaries in an adaptive response to perturbation of hepatic lipid metabolism (43)(44)(45)(46). Consequently, the upregulation of CYP4A we have observed in MCD diet-fed Cyp2e1 -/-mice could be a physiological response in the unusual context of aberrant lipid accumulation and absence of CYP2E1 activity.…”

Concomitant changes in progesterone catabolic enzymes, cytochrome P450 2C and 3A, with plasma insulin concentrations in ewes supplemented with sodium acetate or sodium propionate

“…This time is congruent with the time over which propionate supplementation resulted in increased insulin concentrations. A relationship between insulin and cytochrome P450 expression was proposed when Barnett et al (1990) and Shimojo et al (1993) observed enhanced expression of cytochrome P450 3A during insulin-dependent diabetes, which was reversed by insulin replacement. Saad et al (1994) found a dose-dependent decrease in testosterone hydroxylation at the 6b position when rat hepatocytes were cultured with increasing concentrations of insulin (1, 10 and 100 nM), a reaction that is catalyzed primarily by the cytochrome P450 3A sub-family with minimal contribution from cytochrome P450 2C13 (Ryan and Levin, 1990).…”

Cytotoxic 1-deoxysphingolipids are metabolized by a cytochrome P450-dependent pathway

“…Interestingly, CYP4A and CYP4F genes are differentially regulated by conditions that increase the flux of free fatty acids, such as fasting (47), high-fat diet (48), or T2D (49). CYP4A expression is increased under these conditions, whereas CYP4F expression is decreased.…”