Pulmonary activation and toxicity of cyclopentadienyl manganese tricarbonyl.
Cyclopentadienyl manganese tricarbonyl (CMT) produces acute pulmonary injury following cytochrome P450 mixed-function oxidase (CYP450) activation. The current studies were designed to characterize the role of hepatic and/or pulmonary CMT activation and the subsequent pneumotoxicity of this compound following subcutaneous injection in the male Sprague-Dawley rat. Both pulmonary and hepatic tissues were capable of CYP450-dependent CMT metabolism in vitro. Phenobarbital pretreatment, which induced hepatic but not pulmonary CMT metabolism, protected against CMT-depended pneumotoxicity suggesting escape of an active CMT metabolite from the liver is not responsible for the pneumotoxic response. Animals were also pretreated with either m-xylene or 3-methylindole, each of which reduce CMT metabolism in the lung but not in the liver. These pretreatments also reduced CMT-dependent pulmonary damage. Protection against toxicity by two compounds that inhibit pulmonary but not hepatic CMT metabolism provides strong evidence that CMT-induced pneumotoxicity is due to the activation of CMT within the lungs. Histopathological studies revealed that CMT induced an alveolar injury without apparent damage to the bronchiolar airways. Based on this pattern of injury, studies were performed with freshly isolate alveolar type II (ATII) cells as these cells are thought to contain significant CYP450 activity. However, CMT metabolism was not detectable in ATII cells in vitro. Although CMT was cytotoxic to ATII cells in vitro, this response was not inhibited by metyrapone indicating CYP450 activation was not involved in the in vitro phenomenon. Together these data suggest in situ activation of CMT is necessary for the alveolar toxicity of this compound; however, activation does not occur in ATII cells.
Blanchard
K T
KT
Department of Pathology, Brown University, Providence, Rhode Island 02912, USA.
Clay
R J
RJ
Morris
J B
JB
D000818:Animals; D001711:Biotransformation; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008345:Manganese / Q000378:metabolism; D020149:Manganese Poisoning; D008861:Microsomes / Q000201:enzymology; D009942:Organometallic Compounds / Q000378:metabolism / Q000633:toxicity*; D010634:Phenobarbital / Q000494:pharmacology; D011650:Pulmonary Alveoli / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012862:Skatole / Q000494:pharmacology
D009942:Organometallic Compounds; D011725:Pyridines; C013109:metapyrone; D008345:Manganese; D003577:Cytochrome P-450 Enzyme System; D012862:Skatole; D010634:Phenobarbital; C044679:manganese cyclopentadienyl tricarbonyl