Effects of lindane treatment on drug metabolizing enzymes and liver weight of CF1 mice in which it evoked hepatomas and in non-susceptible rodents.
In CF1 mice lindane treatment led to a significant increase in liver tumor incidence whilst in Osborne-Mendel rats it was not carcinogenic. Although somewhat less clear, the test in B6C3F1 mice led to the conclusion that under the conditions of the bioassay lindane was not carcinogenic for this strain. In this study, the specific activities of some enzymes which are thought to be involved in the metabolism of lindane were studied in these different strains in order to investigate whether differences exist in the activities of these enzymes. Because the enzyme pattern may change after lindane treatment during the carcinogenicity studies, we also investigated the enzyme activities in animals treated for 3 days or 3 months with various doses of lindane. The influence of lindane treatment on the relative liver weight was also determined. B6C3F1 mice showed no increase in absolute or relative liver weight even after 3 months of treatment with the highest tolerated dose of lindane. However, in the susceptible CF1 strain lindane led to a large increase of the absolute and relative liver weight in both sexes, whilst a smaller increase was observed in Osborne-Mendel rats. Basal glutathione-S-transferase activity was higher in males than in females in all three strains, bearing no apparent relationship to susceptibility for tumor formation. However, after treatment with the highest dose of lindane a 5-6-fold induction of this enzyme activity was observed in female CF1 mice, which then together with the male CF1 mice had a higher glutathione-S-transferase activity than untreated and treated B6C3F1 mice and Osborne-Mendel rats. Whether lindane or one of its metabolites is activated by conjugation with glutathione remains to be established. After treatment of the animals with high doses of lindane detergent-treated rat liver microsomes showed a higher UDP-glucuronosyltransferase activity than mouse liver microsomes. This high activity could lead to a rapid conjugation of phenols derived from lindane. The most striking difference observed in this study was the fact that together with the larger increase in absolute and relative liver weight, untreated and treated CF1 mice showed higher monooxygenase activity and, after treatment with lindane, lower epoxide hydrolase activity than rats. Whether the high monooxygenase and rather low epoxide hydrolase activity will lead to an accumulation of reactive epoxides derived from lindane remains to be clarified.
D015660:7-Alkoxycoumarin O-Dealkylase; D000818:Animals; D004851:Epoxide Hydrolases / Q000378:metabolism; D005260:Female; D014453:Glucuronosyltransferase / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D001556:Hexachlorocyclohexane / Q000633:toxicity*; D008099:Liver / Q000187:drug effects*; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000201:enzymology; D008297:Male; D051379:Mice; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D009929:Organ Size / Q000187:drug effects; D010088:Oxidoreductases / Q000378:metabolism*; D010105:Oxygenases / Q000378:metabolism; D051381:Rats; D013045:Species Specificity; D013347:Subcellular Fractions / Q000201:enzymology
D001556:Hexachlorocyclohexane; D006899:Mixed Function Oxygenases; D010088:Oxidoreductases; D010105:Oxygenases; D015660:7-Alkoxycoumarin O-Dealkylase; D014453:Glucuronosyltransferase; D005982:Glutathione Transferase; D004851:Epoxide Hydrolases