Regulation of phenobarbital-inducible cytochrome P-450s in rat and mouse liver following dexamethasone administration and hypophysectomy

Abstract

Cytochrome P-450s are a superfamily of haem-containing proteins involved in the metabolism of foreign compounds, as well as a variety of endogenous molecules. The hepatic levels and function of this diverse group of enzymes are determined by both constitutive and xenobiotic regulators. To examine the role of constitutive factors in cytochrome P-450 regulation, the levels of three distinct groups of phenobarbital-inducible hepatic cytochrome P-450s were studied following dexamethasone-treatment or hypophysectomy. In the mouse, dexamethasone was a potent inducer of proteins within the PB1 (subfamily IIC), PB2c (family III) and PB3 (subfamily IIB) families. These findings were strikingly different from the effects in the rat where essentially no effect on PB3 expression and indeed suppression of proteins related to PB1 was observed. Determination of mRNA concentration indicated that the difference was at the level of transcription. These findings indicate that synthetic glucocorticoids have the potential to be potent phenobarbital-like inducing agents. In the mouse hypophysectomy, like dexamethasone, induced hepatic mRNA of P-450 from families P-450IIB, P-450IIC and P-450III. Again a species difference was observed as this treatment had essentially no effect in the rat. These data in the mouse indicate that factors produced in the pituitary can either affect the transcription rate of phenobarbital and dexamethasone-inducible P-450 genes or influence the stability of their mRNAs.

A novel panel of mouse models to evaluate the role of human pregnane X receptor and constitutive androstane receptor in drug response

“…Treatment of WT and huPXR mice with the potent mouse inducer dexamethasone (DEX) (14,30) resulted in a much more marked consistent induction in WT than in huPXR mice. At doses of up to 10 mg/kg, induction of Cyp3a11 was only observed in WT but not huPXR mice ( Figure 6A).…”

“…The marked species differences in the induction of phase I, II, and III enzymes in response to various compounds raise a difficulty in extrapolating metabolism data across species (30,(38)(39)(40)(41). Taking into account the relevance of drug metabolizing enzyme and transporter induction or repression for drug safety and efficacy, these species differences clearly limit the significance of animal tests in respect to the situation in humans.…”

The role of epoxidation in 4-vinylcyclohexene-induced ovarian toxicity

“…[dexamethasone (Waxman et al, 1985;Wrighton et al, 1985;and Meehan et al, 1988)] forms on the metabolism of VCH and testosterone. In hepatic microsomes isolated from phenobarbital pretreated mice VCH epoxidation was increased 5.7-fold ( Figure 9).…”

In Vivo Responses of the Human and Murine Pregnane X Receptor to Dexamethasone in Mice

“…In addition, submicromolar concentrations of DEX also enhance the expression of the constitutive androstane receptor (CAR) and the retinoid X receptor-␣ in human hepatocytes (Pascussi et al, 2000a,b). It has been shown that DEX is a more potent ligand for mouse PXR than the human receptor (Meehan et al, 1988;Moore et al, 2000), and hepatic induction of Cyp3a, but not Cyp2b, expression in mice is PXRdependent (Schuetz et al, 2000;Scheer et al, 2008).…”

“…In addition, submicromolar concentrations of DEX also enhance the expression of the constitutive androstane receptor (CAR) and the retinoid X receptor-␣ in human hepatocytes (Pascussi et al, 2000a,b). It has been shown that DEX is a more potent ligand for mouse PXR than the human receptor (Meehan et al, 1988;Moore et al, 2000), and hepatic induction of Cyp3a, but not Cyp2b, expression in mice is PXRdependent (Schuetz et al, 2000;Scheer et al, 2008).CYP3A plays a central role in DEX disposition in human liver because it catalyzes the formation of the two major metabolites, 6␣-and 6␤-hydroxy-dexamethasone (Gentile et al, 1996). Indeed, the relatively simple metabolic profile of DEX compared with many other substrates led to the proposal that DEX would be a useful in vivo probe for CYP3A4 activity (Gentile et al, 1996).…”