Modes of action and combination effects of polychlorinated biphenyls and gamma-hexachlorocyclohexane on the regulation of rat liver 3-hydroxy-3-methylglutaryl coenzyme A reductase.

The effect of polychlorinated biphenyls, gamma-hexachlorocyclohexane and the effect of a combination of these substances on the regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase were investigated. As known from previous investigations polychlorinated biphenyls interfere with the regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity in rat liver via enzyme-lipid interaction and at the pretranslational level. In contrast to polychlorinated biphenyls, gamma-hexachlorocyclohexane did not alter the lipid status of the microsomal membrane. Thus the location of the 3-hydroxy-3-methylglutaryl coenzyme A reductase, and consequently the catalytic activity of the enzyme was not changed. As with polychlorinated biphenyls, gamma-hexachlorocyclohexane interacted with enzyme regulation at the pretranslational level. Northern dot hybridization experiments showed a decrease in the level of m-RNA coding for 3-hydroxy-3-methylglutaryl coenzyme A reductase. The effect of combination of gamma-hexachlorocyclohexane and polychlorinated biphenyls was not additive. The gamma-hexachlorocyclohexane effect appeared to play a more important role than that of the polychlorinated biphenyls. The results indicate that the combination effects are as important as the effects of the single compounds when making risk assessments for xenobiotics.