Reactive metabolite formation catalysed by cytochrome P-450j.
Cytochrome P-450j is induced by ethanol, isoniazid, fasting and in diabetes mellitus; the hepatotoxicity of paracetamol and N,N-dimethylnitrosamine is increased following such induction. We have assessed the potential of liver microsomes isolated from control and isoniazid-treated rats to convert some hepatotoxins to reactive metabolites using loss of glutathione, added to microsomal incubations, as an index of reactive metabolite generation. No change or a decrease in glutathione depletion, compared with controls, was found when 4-ipomeanol, cyclophosphamide, toluene, coumarin and butylated hydroxytoluene were incubated with liver microsomes from isoniazid-treated rats. No glutathione depletion was caused by trichloroethylene. Increased glutathione depletion was shown for paracetamol and bromobenzene and their non-hepatotoxic analogues 3-hydroxyacetanilide and p-bromophenol. This confirmed that the glutathione depletion assay fails to distinguish between toxic and non-toxic reactive metabolites. Increased glutathione depletion was also observed for 2-methyl furan, aniline, allyl alcohol, thiophene and chloroform. Analysis of glutathione depletion/concentration relationships demonstrated that P-450j has high affinity for chloroform, as judged by reactive metabolite formation.
Garle
M J
MJ
Department of Physiology and Pharmacology, Medical School, Queen's Medical Centre, Nottingham NG7 2UH, UK.
Fry
J R
JR