Pretranslational down-regulation of male specific hepatic P450s after portal bypass.

Diversion of portal blood away from the liver in the portal vein ligated (PVL) male rat results in dysfunction of the hypothalamo-pituitary-gonadal axis, as reflected by an increase in circulating oestradiol, a decrease in serum testosterone and decreased expression of the male-specific cytochrome P450 2C11 in hepatic microsomes. The present study assessed whether there was a decline in the hepatic concentrations of mRNA species corresponding to male-specific P450s and whether female-specific hepatic enzymes may be upregulated after PVL. In microsomes from PVL male rat liver the activities of P450s 2C11 and 3A2 (androstenedione 16 alpha- and 6 beta-hydroxylation, respectively) were decreased to 45% (P < 0.

Induction of cytochrome P450 2B1 in rat liver by the aromatase inhibitor aminoglutethimide.

Aminoglutethimide (AG) is an inhibitor of P450 aromatase and is in clinical use for the treatment of estrogen-dependent breast cancer in postmenopausal women. AG produces adrenal insufficiency by inhibition of the adrenal P450 cholesterol side chain cleavage enzyme, but a number of serious pharmacokinetic interactions have been reported between AG and coadministered drugs. The present study was undertaken in the rat to assess the modulatory capacity of AG toward P450 enzyme activities in vitro and in vivo and to identify the P450 subject to such effects.

Impaired expression of microsomal cytochrome P450 2C11 in choline-deficient rat liver during the development of cirrhosis.

The microsomal content and activity of the principal male-specific cytochrome P450 2C11 are reduced in cirrhotic rat liver. In order to define the pathophysiological mechanism for such changes, the present study was undertaken to determine the time course of impaired P450 2C11 expression in relation to the development of cirrhosis during intake of a choline-deficient diet. Fatty infiltration of the liver was evident after 6 weeks of intake but hepatic fibrosis was not present until 10 weeks, when fine fibrotic bands in a perisinusoidal distribution were observed.

Increased expression of cytochrome P450 IIIA2 in male rat liver after dietary vitamin A supplementation.

In this study dietary vitamin A supplementation (25 IU/g diet) was assessed for its effect on hepatic microsomal P450 content and on P450 enzyme-specific drug oxidase activities in rats. Intake of the supplemented diet by male rats over a 15-week period resulted in a fivefold increase in hepatic vitamin A stores over those measured in control liver from rats that received a balanced diet without vitamin A supplementation. Serum retinol was unchanged and there was no evidence of hepatocellular injury in any of the animals.

Rat but not human interferons suppress hepatic oxidative drug metabolism in rats.

An animal model suitable for in vivo studies of interferon-mediated suppression of hepatic oxidative drug metabolism has been developed. Rats were injected with either recombinant human interferon alpha A, recombinant human interferon gamma, recombinant rat interferon gamma, or vehicle and experiments were performed 24 h later. In some animals theophylline elimination was determined twice (10 days apart), once after interferon and once after vehicle.