Inhibition of methyl chloride toxicity in male F-344 rats by the anti-inflammatory agent BW755C.
This study examined the effectiveness of the cyclooxygenase/lipoxygenase inhibitor 3-amino-1-[m-(trifluoromethyl)phenyl]-2-pyrazoline (BW755C) in preventing the toxicity induced in male F-344 rats by methyl chloride (MeCl). BW755C (10 mg/kg ip, 1 hr pre and postexposure) prevented both lethality (0/6 vs 8/12 in controls) and epididymal granuloma formation (0/6 vs 4/4 in controls) in rats exposed to 7500 ppm MeCl 6 hr/day for 2 days. Additional rats (n = 5 per group) were exposed to 5000 ppm MeCl 6 hr/day for 5 days, with and without BW755C treatment as described above. The rats were killed on Day 5 and tissues processed for light microscopic examination. MeCl-exposed rats showed hepatocellular cloudy swelling, degeneration of renal proximal convoluted tubules, vacuolar degeneration in the adrenal cortex, necrosis of the internal granular layer of the cerebellum, and degenerative changes in the testis and epididymis, including formation of epididymal sperm granulomas. With the exception of the adrenal, tissues examined in rats of the MeCl/BW755C treatment group showed virtually no histologic evidence of lesions. BW755C did not significantly alter metabolism of [14C]MeCl to 14CO2 or 14C in urine, nor did it affect the distribution to various organs of radioactivity derived from [14C]MeCl. Therefore, BW755C protection against MeCl toxicity did not appear to result from altered MeCl metabolism or disposition. Instead, the protection was apparently related to the pharmacologic activity of BW755C as an inhibitor of leukotriene and prostaglandin synthesis.
D015772:4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001835:Body Weight / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004822:Epididymis / Q000187:drug effects; D008297:Male; D008737:Methyl Chloride / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000633:toxicity; D011720:Pyrazoles / Q000494:pharmacology*; D051381:Rats; D014018:Tissue Distribution
D000894:Anti-Inflammatory Agents, Non-Steroidal; D011720:Pyrazoles; D015772:4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine; D008737:Methyl Chloride