Effect of carbon-monoxide on xenobiotic metabolism in the isolated perfused rabbit lung
Abstract
Carbon monoxide is an environmental pollutant and a known inhibitor of cytochrome P-450-mediated reactions in in vitro preparations. The influence that carbon monoxide has on mixed function oxidase activity in the intact animal and isolated organ systems has been studied less extensively. The effect of carbon monoxide on mixed function oxidase activity was investigated in the isolated perfused lung because this organ is the port of entry for CO into the body, and it possesses an active xenobiotic metabolizing system that contributes to the disposition of circulating substances in the intact animal. It was the aim of this study to determine the level and duration of CO exposure necessary to alter mixed function oxidase-mediated activity in the intact lung and to determine the magnitude of this effect. The effect of CO on the mixed function oxidase-mediated activities of aminopyrine, aniline, 4-ipomeanol and p-nitroanisole in isolated perfused rabbit lungs (IPRL) was investigated. Several concentrations of CO (7.5%, 1.0% and 0.1% in 20% O$\sb2$) were evaluated for their effect on cytochrome P-450-mediated activity in the lung. Both artificial medium and whole blood were utilized as recirculating perfusates. Monomethyl-4-aminoantipyrine was the major metabolite of aminopyrine produced by in vitro hepatic and pulmonary preparations and by the intact lung. Ventilation of isolated rabbit lungs with 7.5% CO for 2.5 hours caused a 40% decrease in the rates of metabolism of both aminopyrine and p-nitroanisole. This level of CO exposure did not alter the cytochrome P-450-mediated metabolism of aniline nor 4-ipomeanol in the intact lung. Aminopyrine metabolism in isolated rabbit lungs perfused with whole blood was also decreased following the administration of 7.5% CO suggesting that the hemoglobin in whole blood affords no protection against CO-induced inhibition of mixed function oxidase activity in the intact lung. The isozyme of cytochrome P-450 which preferentially metabolizes aminopyrine and p-nitroanisole may be more sensitive to CO-induced inhibition than the form(s) which metabolize aniline and 4-ipomeanol.
Degree
Ph.D.
Advisors
Carlson, Purdue University.
Subject Area
Pharmacology
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