Potentiation of atracurium toxicity in isolated rat hepatocytes by inhibition of its hydrolytic degradation pathway.
This study tested the hypothesis that the esters of acrylic acid might be responsible for the previously observed cytotoxic effect of atracurium. Rats were pretreated with triorthotolyl phosphate (TOTP), an inhibitor of the hydrolytic degradation of atracurium. Because hydrolysis of acrylates is also inhibited by TOTP and because the hydrolysis represents a detoxification pathway for these esters, we postulated that the leak of lactic dehydrogenase (LDH) induced by atracurium would be enhanced in hepatocytes harvested from rats pretreated with TOTP. Hepatocytes isolated from rats previously treated with TOTP (25 or 50 mg/kg intraperitoneally, 20 hr before induced death) were incubated for 4 hr in the absence of muscle relaxants or in the presence of either atracurium (0.008-0.8 mM) or metocurine (0.015-0.85 mM). Atracurium produced a concentration-dependent leakage of LDH. The leakage out of cells obtained from TOTP-pretreated rats was greater than was the leakage out of hepatocytes harvested from animals pretreated only with corn oil (a vehicle for TOTP). Metocurine did not produce a leak of LDH. It is concluded that the LDH leakage was produced by ester-type products of atracurium degradation. Acrylates appear to be the toxic agent.
D000179:Acrylates / Q000378:metabolism; D000818:Animals; D001279:Atracurium / Q000378:metabolism / Q000633:toxicity*; D002384:Catalysis; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006868:Hydrolysis; D007770:L-Lactate Dehydrogenase / Q000037:antagonists & inhibitors / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D014317:Tritolyl Phosphates / Q000494:pharmacology; D014403:Tubocurarine / Q000031:analogs & derivatives / Q000378:metabolism / Q000633:toxicity
D000179:Acrylates; D014317:Tritolyl Phosphates; D001279:Atracurium; D007770:L-Lactate Dehydrogenase; C032943:metocurine; D014403:Tubocurarine; C025541:tri-o-cresyl phosphate