PULMONARY ACTIVATION AND TOXICITY OF CYCLOPENTADIENYL MANGANESE TRICARBONYL

Cyclopentadienyl manganese tricarbonyl (CMT) produces acute pulmonary injury following cytochrome P450 mixed-function oxidase (CYP450) activ ation. The current studies were designed to characterize the role of h epatic and/or pulmonary CMT activation and the subsequent pneumotoxici ty of this compound following subcutaneous injection in the male Sprag ue-Dawley rat. Both pulmonary and hepatic tissues were capable of CYP4 50-dependent CMT metabolism in vitro. Phenobarbital pretreatment, whic h induced hepatic but not pulmonary CMT metabolism, protected against CMT-depended pneumotoxicity suggesting escape of an active CMT metabol ite from the liver is not responsible for the pneumotoxic response, An imals were also pretreated with either m-xylene or 3-methylindole, eac h of which reduce CMT metabolism in the lung but not in the liver. The se pretreatments also reduced CMT-dependent pulmonary damage. Protecti on against toxicity by two compounds that inhibit pulmonary but not he patic CMT metabolism provides strong evidence that CMT-induced pneumot oxicity is due to the activation of CMT within the lungs, Histopatholo gical studies revealed that CMT induced an alveolar injury without app arent damage to the bronchiolar airways, Based on this pattern of inju ry, studies were performed with freshly isolated alveolar type II (ATI I) cells as these cells are thought to contain significant CYP450 acti vity, However, CMT metabolism was not detectable in ATII cells in vitr o. Although CMT was cytotoxic to ATII cells in vitro, this response wa s not inhibited by metyrapone indicating CYP450 activation was not inv olved in the in vitro phenomenon, Together these data suggest in situ activation of CMT is necessary for the alveolar toxicity of this compo und; however, activation does not occur in ATII cells. (C) 1996 Academ ic Press, Inc.