Upregulation of cytochromes P450 2B in rat liver by orphenadrine

Abstract

1 The alkylamine drug orphenadrine (ORPH) is an inducer and inhibitor of the microsomal cytochrome P450 (CYP) system in mammals. This study evaluated the selectivity of CYP induction by ORPH in rat liver. 2 Immunoblot analysis indicated that ORPH was a selective inducer of the phenobarbitone (PB)-inducible CYP2B in rat liver. CYP2B protein was increased to B14-fold of levels in untreated rat liver. By comparison PB increased CYP2B expression 40-fold. Corresponding increases in the activity of CYP2B-dependent androstenedione 16b-hydroxylation were measured in microsomes from ORPH and PB-induced rats. 3 Northern analysis indicated that CYP2B1/2 mRNA was increased in ORPH-induced rat liver. Consistent with this finding, ORPH was found to activate a PB-responsive enhancer module in constitutive androstane receptor (CAR)-transfected Hep G2 cells. 4 Other alkylamines like troleandomycin impair CYP turnover. We tested whether ORPH induction of CYP2B may include a post-translational component. In PB-pretreated animals ORPH administration delayed the loss of CYP2B after PB withdrawal, but no evidence for altered turnover was found. 5 These studies establish ORPH as a selective inducer of CYP2B in rat liver. Induction appears to be mediated pretranslationally by CAR activation of CYP2B gene transcription. Post-translational stabilisation by an ORPH metabolite does not elicit induction. Induction of CYP2B may influence pharmacokinetic interactions involving ORPH.

Liver tumor promoting effect of orphenadrine in rats and its possible mechanism of action including CAR activation and oxidative stress

“…It has been known that the CAR is related to CYP2B induction of ORPH (Murray et al, 2003). In the present study, immunohistochemistry revealed that nuclear translocation of CAR was increased by ORPH treatment.…”

“…Two weeks after the partial hepatectomy one rat in the control group died. For selection of the ORPH dosage we referred to a previous report (Murray et al, 2003). The highest dosage in our study was set at half of the dosage calculated from the report because of the taste of ORPH.…”

Enhanced liver tumor promotion activity in rats subjected to combined administration of phenobarbital and orphenadrine

“…It is used in the early stages of Parkinson's disease because of its skeletal muscle relaxant properties (Brocks, 1999). In contrast, it has been demonstrated that ORPH induces CYP2B in the livers of rats (Murray et al, 2003) and has a liver tumor-promoting effect in rats attributable to oxidative DNA damage resulting from an increase in microsomal ROS production (Morita et al, 2013).…”

Role of CYP pharmacogenetics and drug-drug interactions in the efficacy and safety of atypical and other antipsychotic agents

“…The PXR is activated by a wide range of chemicals, including dexamethasone, rifampicin and carbamazepine, and induces CYPs 3A (Xie et al 2000;Watkins et al 2001). CYP2B genes are inducible by phenobarbital, orphenadrine and other drugs that activate the CAR (Murray et al 2003;Wang & Negishi 2003). In principle, SNPs in 5 0 -upstream regulatory regions in CYP genes may influence the extent of induction by altering the binding of ligand-activated transcription factors to important regulatory elements.…”