Study of the mutagenic activity of 6 hepatotoxic pharmaceutical drugs in the Salmonella typhimurium microsome test, and the HGPRT and Na+/K+ ATPase system in cultured mammalian cells.
Several pharmaceutical drugs show strong hepatotoxicity during therapeutic use. We have studied 6 of them: aminophenazone, clofibrate, nifuroxazide, oxamniquine, perhexiline maleate, tienilic acid. Their mutagenicity was assessed in the Ames test on 6 strains of Salmonella typhimurium, and in V79 Chinese hamster lung cells using a rat-hepatocyte-mediated metabolic activation system and the HGPRT and Na+/K+ ATPase assay. Nifuroxazide was positive in the Ames test in two Salmonella strains (TA100, and TA100 Fr1). In the hepatocyte-mediated mammalian V79 cell system, nifuroxazide, clofibrate and aminophenazone were negative; oxamniquine and tienilic acid were positive with and without metabolic activation in tests looking for ouabain and 6-thioguanine resistance. Perhexiline maleate was negative for the direct induction of 6-thioguanine resistance without metabolic activation, and positive after metabolisation mediated by primary rat's hepatocytes. These results suggest the need for some caution in the use of some pharmaceutical drugs because of hepatotoxicity and because 3 out of 6 drugs were shown to be slightly mutagenic in mammalian cells.
Dayan
J
J
Deguingand
S
S
Truzman
C
C
D000632:Aminopyrine / Q000494:pharmacology*; D000818:Animals; D001711:Biotransformation; D002460:Cell Line; D002994:Clofibrate / Q000494:pharmacology*; D006224:Cricetinae; D003412:Cricetulus; D004351:Drug Resistance; D006016:Glycolates / Q000494:pharmacology*; D007041:Hypoxanthine Phosphoribosyltransferase / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000473:pathology*; D008168:Lung; D008862:Microsomes, Liver / Q000378:metabolism; D009152:Mutagenicity Tests / Q000379:methods; D009153:Mutagens; D009154:Mutation; D009581:Nitrofurans / Q000494:pharmacology*; D009600:Nitroquinolines / Q000494:pharmacology*; D010042:Ouabain / Q000494:pharmacology; D010073:Oxamniquine / Q000494:pharmacology*; D010480:Perhexiline / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D012486:Salmonella typhimurium / Q000187:drug effects; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism*; D013866:Thioguanine / Q000494:pharmacology; D013989:Ticrynafen / Q000494:pharmacology*
D006016:Glycolates; D009153:Mutagens; D009581:Nitrofurans; D009600:Nitroquinolines; D000632:Aminopyrine; D010073:Oxamniquine; D010042:Ouabain; D007041:Hypoxanthine Phosphoribosyltransferase; D000254:Sodium-Potassium-Exchanging ATPase; D013866:Thioguanine; D013989:Ticrynafen; D002994:Clofibrate; D010480:Perhexiline