title: Effect of chronic alcohol drinking on rat liver microsomal nitroreductive metabolism of nifurtimox and benznidazole.
abstract: Nifurtimox (Nfx) and benznidazole (Bz) have serious toxic side effects. Manufacturers warn about significant adverse effects when simultaneous alcohol consumption is being made, but its mechanism is not known. The levels and toxicity of these drugs are linked to their liver microsomal nitroreduction to reactive metabolites. In this study, we analyzed whether alcohol drinking enhanced those nitroreductive processes. Male and female Sprague-Dawley rats, 5-6 weeks old (125-150 g body weight) were used. They were fed ad libitum for 28 days with Lieber and De Carli control or alcohol regular liquid diets. The rats were separated into two dietary groups: ethanol and control group. Both were pair fed with the respective diet. Their liver microsomes were isolated and the nicotinamide adenine dinucleotide phosphate-dependent nitroreduction of Nfx and Bz were determined. Alcohol drinking significantly induced microsomal nitroreduction of these drugs in male rats (11% for Nfx and 41% for Bz) but not in females. The activity observed in the alcohol-induced male rats was 100% inhibited by diphenyleneiodonium and attributable to P450 reductase. Inductive effects of alcohol drinking on nitroreductive activation of both drugs might be only partially involved in the harmful interactions described.
authors.affiliation: 1Centro de Investigaciones Toxicológicas (CEITOX) CITEDEF-CONICET (UNIDEF), Juan B. de La Salle 4397, Villa Martelli, Argentina.
authors.forename: M M
authors.initials: MM
authors.lastname: de Mecca
authors.forename: L C
authors.initials: LC
authors.lastname: Bartel
authors.forename: J A
authors.initials: JA
authors.lastname: Castro
mesh_terms: D000428:Alcohol Drinking / Q000009:adverse effects*; D000818:Animals; D004347:Drug Interactions; D005260:Female; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism; D009547:Nifurtimox / Q000633:toxicity*; D009593:Nitroimidazoles / Q000633:toxicity*; D009601:Nitroreductases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014344:Trypanocidal Agents / Q000633:toxicity*
chemical_list: D009593:Nitroimidazoles; D014344:Trypanocidal Agents; D009601:Nitroreductases; D009547:Nifurtimox; C009999:benzonidazole
keywords: Alcohol drinking; Nifurtimox; benznidazole; liver microsomes; nitroreduction