Co-administration of ethanol transiently inhibits urethane genotoxicity as detected by a kinetic study of micronuclei induction in mice.
Urethane (ethyl carbamate) is a genotoxic carcinogen that requires metabolic activation. Ethanol is known to inhibit urethane metabolism and genotoxicity. Since ethanol is eliminated rapidly in animals, the persistence of ethanol inhibition was studied in a mouse bone marrow and a peripheral blood micronucleus assays. In the bone marrow assay, male CD-1 mice were injected intraperitoneally (i.p.) with water (vehicle), urethane (1000 mg/kg), ethanol (2500 mg/kg) or urethane and ethanol (1000 and 2500 mg/kg, respectively) in single injections. Polychromatic erythrocytes (PCE) from bone marrow were obtained at 24 and 48 h after injection and scored for micronuclei. Urethane induced an increase of micronucleated PCE (MN PCE) frequency from 0.19% in the control to 8.63% at 24 h, followed by a decrease to 6.98% at 48 h. When urethane was co-administered with ethanol, the MN PCE frequency was suppressed to 0.49% at 24 h, but markedly increased to 7.35% at 48 h. This delay of MN PCE occurrence indicated that ethanol inhibition was transient. To pinpoint the duration of this delay, a peripheral blood micronucleus assay was conducted to monitor the kinetics of MN PCE induction. In this assay, male CD-1 mice were injected i.p. with water, ethanol, urethane, or urethane and ethanol as described above. Peripheral blood was scored for MN PCE at 8-h intervals for 4 days. Two additional dose groups injected with urethane or urethane and ethanol were also scored for MN PCE at 8 h intervals, but each blood sampling time was staggered 4 h later from the first four dose groups. The combined data provided MN PCE frequencies at 4-h intervals from 24 to 100 h after injection. Urethane alone induced a peak MN PCE frequency of 11.6% at 52 h. Urethane and ethanol induced a peak MN PCE frequency of 11.2% at 64 h, a delay of 12 h. Thus, ethanol delays but does not diminish urethane genotoxicity.
Choy
W N
WN
Safety Evaluation Center, Schering-Plough Research Institute, Lafayette, NJ 07848, USA.
Mandakas
G
G
Paradisin
W
W
D000818:Animals; D001853:Bone Marrow / Q000187:drug effects; D002273:Carcinogens / Q000633:toxicity*; D004347:Drug Interactions; D004912:Erythrocytes / Q000187:drug effects; D000431:Ethanol / Q000008:administration & dosage / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D048629:Micronuclei, Chromosome-Defective / Q000187:drug effects*; D015162:Micronucleus Tests; D009153:Mutagens / Q000633:toxicity*; D014520:Urethane / Q000633:toxicity*
D002273:Carcinogens; D009153:Mutagens; D014520:Urethane; D000431:Ethanol