Comparative pneumotoxicity of cyclopentadienyl manganese tricarbonyl and methylcyclopentadienyl manganese tricarbonyl.
The acute pneumotoxic effects of cyclopentadienyl manganese tricarbonyl (CMT) and methylcyclopentadienyl manganese tricarbonyl (MMT) were compared to delineate the role of the methyl side chain in the toxicity of these organomanganese compounds and to further our understanding of the mechanisms by which these compounds act. Specifically, lung manganese (Mn) burdens and the pneumotoxic response, as measured by bronchoalveolar lavage parameters, were determined in male Sprague-Dawley rats 24 hr after sc administration of 0.5, 1.0, or 2.5 mg Mn/kg as CMT or MMT. The pneumotoxic response to either compound was characterized by large increases in lavage albumin and protein content with smaller increases in lactate dehydrogenase levels. CMT was approximately twice as potent as MMT. This difference in potency may be due to methyl side chain oxidation, a metabolic detoxification pathway unavailable to CMT. Lung Mn content was significantly elevated after treatment with either CMT or MMT. Heptane extraction studies revealed that Mn was accumulated in a nonlipid soluble form, suggesting the accumulation of metabolites rather than heptane soluble parent MMT or CMT. A strong correlation between pulmonary Mn content and toxicity was observed, suggesting a causal relationship between the accumulation of CMT or MMT metabolites and toxicity. Piperonyl butoxide diminished both the pneumotoxicity and Mn accumulation resulting from CMT or MMT, suggesting both phenomena are due to monooxygenase metabolites. Pulmonary nonprotein sulfhydryl (NPSH) levels were increased twofold 24 hr after administration of either CMT or MMT. Depletion of NPSH was not observed 1.5 or 6 hr after administration. The mechanisms of this response are unclear but may be due to the metabolism of CMT or MMT to unstable compounds which release inorganic Mn within pulmonary cells.
Clay
R J
RJ
Toxicology Program, School of Pharmacy, University of Connecticut, Storrs 06268.
Morris
J B
JB
D000418:Albumins / Q000032:analysis; D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology; D007770:L-Lactate Dehydrogenase / Q000032:analysis; D008168:Lung / Q000032:analysis / Q000187:drug effects*; D008297:Male; D008345:Manganese / Q000032:analysis; D009942:Organometallic Compounds / Q000378:metabolism / Q000633:toxicity*; D051381:Rats; D013438:Sulfhydryl Compounds / Q000032:analysis
D000418:Albumins; D009942:Organometallic Compounds; D013438:Sulfhydryl Compounds; C009907:2-methylcyclopentadienyl manganese tricarbonyl; D008345:Manganese; D003577:Cytochrome P-450 Enzyme System; D007770:L-Lactate Dehydrogenase; C044679:manganese cyclopentadienyl tricarbonyl