Dimethylsulfoxide as modifier of the organospecific mutagenicity of metronidazole in mice.
Mutagenicity and carcinogenicity of metronidazole (MT) are imputable to the formation of toxic intermediates, which include radical forms derived from the nitroreductive process. Since dimethylsulfoxide (DMSO), the "universal" solvent, can quench free radicals in vitro, it was suggested that DMSO might protect by scavenging free radical generation in vivo. This study wanted to evaluate if DMSO (given concomitantly or prophylactically) protects against the organospecific mutagenicity of MT in vivo by means of the intrasanguineous host-mediated assay. DMSO used as solvent showed a 20%-30% reduction in the mutation frequencies by MT. Prophylactic administration of DMSO for 3 d caused a suppression of the organospecific mutagenicity. However, some increases in the spontaneous mutation frequency and enhancement of MT mutagenicity in kidney were observed. The protective effect was paralleled by a decrease in NADPH cytochrome c (P450) reductase in liver, kidney, and to a lesser extent in lung microsomes from pretreated mice. Inhibition of mutagenic activity might be related to scavenging of radical species as supported by the lack of tissue specificity and no appreciable changes in specific enzyme activity. However, changes in reductase content in prophylactically pretreated mice can affect the quantitative biotransformation of MT to the proximal mutagen contributing to the observed suppression in mutation frequencies.
Hrelia
P
P
Istituto di Farmacologia, Università degli Studi, Bologna, Italy.
Scotti
M
M
Morotti
M
M
Vigagni
F
F
Paolini
M
M
Sapigni
E
E
Cantelli-Forti
G
G
D000818:Animals; D001711:Biotransformation / Q000187:drug effects; D004121:Dimethyl Sulfoxide / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects / Q000201:enzymology; D008099:Liver / Q000187:drug effects; D008168:Lung / Q000187:drug effects / Q000201:enzymology; D008297:Male; D008795:Metronidazole / Q000493:pharmacokinetics / Q000633:toxicity*; D051379:Mice; D008861:Microsomes / Q000201:enzymology; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D009152:Mutagenicity Tests; D009154:Mutation; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism
D008795:Metronidazole; D009251:NADPH-Ferrihemoprotein Reductase; D004121:Dimethyl Sulfoxide