Disease, Metabolism and Reproduction in the Toxic Response by T. Godfraind (auth.), Philip L. Chambers, Paolo Preziosi,

By T. Godfraind (auth.), Philip L. Chambers, Paolo Preziosi, Claire M. Chambers (eds.)

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Additional resources for Disease, Metabolism and Reproduction in the Toxic Response to Drugs and Other Chemicals: Proceedings of the European Society of Toxicology Meeting Held in Rome, March 28 – 30, 1983

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1971; Nishikimi 1975) and with ethylenediamine which is a known a-quinone trapping agent (Jellinck and Irwin 1963). The possible involvement of quinone or semiquinone intermediates in macromolecular binding was also indicated by the enhancement of the NADPH-dependent rate of [3- 14C] coumarin metabolite binding by mushroom tyrosinase, an enzyme which possesses a variety of oxidase activities (Zeffren and Hall 1973). The lack of effect of this enzyme in the absence of an NADPH-generating system indicates that it is activating a metabolite of coumarin rather than the parent compound, although it remains to be demonstrated that mushroom tyrosinase leads to the formation of the same reactive metabolite or metabolites as are produced by an NADPH-generating system alone.

The prolonged prothrombin time in patients treated with coumarin-type anticoagulants concurrently suffering from hyperthyroidism seems to be the result of a increased catabolism of the vitamin K-dependent clotting factors, rather than inhibition of drug metabolism of the anticoagulants. In hypothyroid patients their hypothrombinaemic action is decreased due to an unusually slow rate of decay of the vitamin K-dependent clotting factors (Self et al. 1975). 44 M.

The inhibition obtained with hepatic cytosol fractions may have been due to both the presence of reduced NPS compounds and to the action of glutathione S-transferase enzymes. Investigations into the kinetics of macromolecular binding revealed a biphasic plot which may indicate either the participation of multiple cytochrome P-450 forms in the bioactivation process or the formation of two or more distinct reactive intermediates. However, in the inhibition studies essentially similar effects were observed on both kinetic processes.

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