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CR Wolf, CN Statham, MG McMenamin, JR Bend, MR Boyd and RM Philpot
Metabolism of the pulmonary toxin, 4-ipomeanol, in microsomal preparations from rabbit liver and lung and in purified cytochrome P- 450-dependent monooxygenase systems was investigated. The rate of formation of reactive electrophilic products from 4-ipomeanol was estimated by measuring covalent binding to protein or glutathione. Pulmonary microsomal preparations were much more active than hepatic preparations in mediating these reactions. Both of the rabbit pulmonary cytochrome P-450 isozymes, P-450I and P-450II, were active in the metabolism of 4-ipomeanol. In the assay for covalent binding to protein, P-450I was slightly more active than P-450II at high substrate concentrations and significantly more active at low substrate concentrations. Incubation of either isozyme with 4-ipomeanol produced two glutathione conjugates but at quite different ratios. Rates of metabolism determined by conjugate formation in the purified systems were about 3 times the rates determined by covalent binding to protein, whereas both determinations gave the same values in the microsomal preparations. The relationship between the activities of P-450I and P- 450II in the metabolism of 4-ipomeanol and the pulmonary toxicity of 4- ipomeanol is discussed.
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