Novobiocin Inhibits Both UDP-Glucuronosyltransferase and Cytochrome P450-Mediated Enzyme Activities in Pig Liver Microsomes

Authors: Villar D.1; Furusawa N.2; Monshouwer M.3; Van Miert A.S.J.P.A.M.3

Source: Veterinary Research Communications, Volume 22, Number 6, September 1998 , pp. 405-414(10)

Publisher: Springer

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Abstract:

The effects of novobiocin (range 0.0125–2 mmol/L) on the hydroxylation of testosterone, the N-demethylation of erythromycin, and the glucuronidation of agr-naphthol and paracetamol were studied using pig hepatic microsomes, pooled from five animals. The final concentrations of these substrates in the incubation mixtures were selected to meet V_max conditions. Novobiocin caused a concentration-dependent inhibition of the glucuronidation of paracetamol; the formation of agr-naphthol-glucuronide was reduced to a lesser degree. These results confirm and extend earlier findings in laboratory animal species that novobiocin inhibits UDP-glucuronosyltransferases (UDPGTs). Moreover, novobiocin strongly inhibited 6bgr-hydroxylation of testosterone. The microsomal N-demethylation of erythromycin and hydroxylation of testosterone at the 15agr position were less affected by novobiocin. These results suggest that novobiocin inhibits not only UDPGTs, but also cytochrome P450 (CYP) enzyme activities, probably those belonging to the CYP3A subfamily. More research is needed to reveal which CYPs and UDPGTs are affected by novobiocin in vivo, in order to improve the understanding and probably the predictability of potential drug interactions with this antibiotic.

Keywords: cytochrome P450; drug interactions; novobiocin; pig; UDP-glucuronosyltransferase

Language: English

Document Type: Regular paper

Affiliations: 1: The MaCaulay Land Use Research Institute, Aberdeen, UK 2: Department of Food and Nutrition, Division of Experimental Food Science, Faculty of Human Life Science, Osaka City University, Osaka, Japan 3: Department of Basic Sciences, Division of Veterinary Pharmacology, Pharmacy and Toxicology, Faculty of Veterinary Medicine, Utrecht University, PO Box 80176, NL-3508 TD Utrecht, The Netherlands

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