o,p'-DDD in the mouse lung: selective uptake, covalent binding and effect on drug metabolism.
By means of autoradiography a high and selective accumulation was observed in the lung alveolar region of C57Bl mice injected with o,p'-[14C]DDD. Exhaustive extraction of lung tissue showed that a large fraction of the radioactivity was covalently bound to protein. Covalent binding in liver was 20-30 times lower and represented a smaller fraction of the total radioactivity present in this tissue. Formation of a cytochrome P-450 catalysed reactive metabolite in lung and liver was indicated by a decreased covalent binding in these tissues in mice pretreated with metyrapone. Both beta-naphthoflavone (beta NF) and phenobarbital (PB) pretreatment decreased binding of o,p'-DDD in lung tissue, while binding in the liver was induced by PB but remained unaffected by beta NF. Pretreatment with high doses of o,p'-DDD and p,p'-DDT gave a significantly decreased binding of o,p'-[14C]DDD in lung, whereas binding in liver remained unchanged. Conjugation with glutathione does not appear to be a major inactivation pathway for the reactive lung metabolite, since a high dose of o,p'-DDD did not deplete non-protein thiols (NPSH) in lung tissue. Pretreatment with o,p'-DDD decreased the N-demethylation of [dimethyl-14C]aminopyrine in both lung and liver in a dose-dependent manner, suggesting that the drug-metabolizing enzyme system may be a target for o,p'-DDD in vivo.
D000273:Adipose Tissue / Q000378:metabolism; D000311:Adrenal Glands / Q000378:metabolism; D000632:Aminopyrine / Q000378:metabolism; D000818:Animals; D001345:Autoradiography; D001571:Benzoflavones / Q000494:pharmacology; D003634:DDT / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D007536:Isomerism; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000378:metabolism*; D008298:Maleates / Q000494:pharmacology; D008797:Metyrapone / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008939:Mitotane / Q000378:metabolism*; D010634:Phenobarbital / Q000494:pharmacology; D011650:Pulmonary Alveoli / Q000378:metabolism*; D019324:beta-Naphthoflavone
D001571:Benzoflavones; D008298:Maleates; D000632:Aminopyrine; D019324:beta-Naphthoflavone; D008939:Mitotane; D003634:DDT; C014476:diethyl maleate; D010634:Phenobarbital; D008797:Metyrapone