Pulmonary xenobiotic conjugation in the isolated perfused rabbit lung and in vitro: Effects of carbon monoxide and ethanol
Abstract
Pulmonary conjugation pathways may be important for the metabolism of xenobiotics introduced via airways or systemically. The objective of this study was to determine the pulmonary conjugating capacity in both the isolated perfused rabbit lung (IPRL) and in vitro, and the ability of carbon monoxide (CO) and ethanol to alter the above. The IPRL was capable of conjugating glutathione (GSH) with either 1-chloro-2,4-dinitrobenzene (CDNB) or 1,2-epoxy-(p-nitrophenoxy)propane (ENP). The pulmonary GSH conjugation with ENP was inhibited by cibacron blue, indicating the presence of glutathione-S-transferase (GST) $\mu$ and/or $\pi$ classes, but it was not altered by buthionine sulfoximine, a selective inhibitor of $\gamma$-glutamylcysteine synthetase. The specific activity of cytosolic GST with CDNB and 3,4-dichloronitrobenzene (DCNB) in the rabbit lung was approximately 10% that in the rabbit liver. Neither glucuronide nor sulfate conjugates of 1-naphthol (1-NT) were found in the IPRL. About 35% of the initial 7-hydroxycoumarin (7-HC) was conjugated, the majority being sulfate conjugate (14.4 nmoles/hr) with minor amounts (0.12%) of the glucuronide. In vitro, glucuronidation with 1-NT, 7-HC, 4-nitrocatechol and phenolphthalein and sulfation with 1-NT in rabbit lungs were 20% to 40% of those determined in the liver. CO at a concentration of 7.5% did not alter the rate of GSH conjugation with ENP in the IPRL. In the same system, acute ethanol treatment decreased the maximal rate of GSH conjugation with CDNB, whereas chronic treatment increased it. None of these ethanol treatments altered GSH conjugation with ENP or pulmonary GSH content. In in vitro studies in rats, acute ethanol administration decreased hepatic GSH content and GST activity in both liver and lung, which were accompanied by increased plasma GSH content and GST activity. Chronic ethanol treatment increased hepatic GSH content. No simple link between alteration in GST activity and lipid peroxidation and/or induction of microsomal enzyme activity was identified. Ethanol did not alter glucuronidation or sulfation in vitro in either liver or lung.
Degree
Ph.D.
Advisors
Carlson, Purdue University.
Subject Area
Pharmacology|Toxicology
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