Studies in drug hepatotoxicity.

Abstract

The effects of seven oral contraceptive steroids and the compounds sodium fusidate, (+)-catechin and methyl methacrylate were studied on the glucuronide conjugation of bilirubin and 2-aminophenol using rat liver slice and microsome preparations. The effects of these substances on the hepatic microsomal enzymes, UDP glucuronyl transferase, glucose-6-phosphatase, NADH and NADPH cytochrome reductases and diaphorase were studied using rat liver microsomes. The influence of the drugs on enzyme kinetics was investigated whereover possible. Of the oral contraceptive steroids, the oestrogen, ethynyl oestradiol, inhibited bilirubin and 2-aminophenol conjugation in rat liver slices and UDP glucuronyl transferase in microsomes. No oral contraceptive steroid affected the other enzymes tested. Most oral contraceptive tablets contain either ethynyl oestradiol or mestranol. Since mestranol and many progestogens are metabolised to ethynyl oestradiol, the effects may be more significant than is first apparent. Sodium fusidate inhibited the conjugation of bilirubin and 2-aminophenol in rat liver slices. Using rat liver microsomes the effects on UDP glucuronyl transferase were twofold. Using bilirubin as substrate, at drug concentrations 0.5 - 5.0mM, activation occured but inhibition was produced at higher concentrations. Using 2-amino-phenol as substrate, activation was produced by 0.5 - 1.0mM sodium fusidate with inhibition at higher concentrations. The drug was a non-competitive inhibitor of all enzymes tested with a competitive component in the case of glucose-6-phosphatase. Surfactant properties of the drug greatly influenced its affect on enzymes and may be implicated in toxic effects. (+)-Catechin competitively inhibited microsomal UDP glucuronyl transferase but inhibition was only significant in slice experiments when 2-aminophenol was used as substrate. High drug concentrations inhibited glucose-6-phosphatase uncompetitively but not adenosine triphosphatase. (+)-Catechin inhibited NADPH and NADH cytochrome c reductases, the latter by mixed-type mechanism. At concentrations up to 10mM Methyl methacrylate did not affect any of the enzymes studied.

Date of Award	1975
Original language	English
Awarding Institution	University of Bath