Biochemical effects of the mouse hepatocarcinogen oxazepam: similarities to phenobarbital.
The National Toxicology Program (NTP) recently determined that the commonly prescribed sedative hypnotic agent oxazepam is a mouse liver carcinogen. Many other benzodiazepines are metabolized to oxazepam resulting in further human exposure to this drug. This has resulted in considerable interest in the mechanism of oxazepam-mediated mouse liver carcinogenesis for use in human risk assessment. Several directions for mechanistic research were examined in this study. B6C3F1 mice were treated with oxazepam-dosed feed at 125 (noncarcinogenic) and 2500 ppm (carcinogenic) for 3, 7, 10, and 21 days. Cell proliferation in liver, cytochrome P450 induction, free radical formation, GSH depletion, and levels of circulating thyroid-stimulating hormone (TSH) were analyzed at these time points. Increased levels of hepatic cell proliferation were observed by 7 days at 125 ppm and by 10 days at 2500 ppm. Microsomal enzyme induction also occurred and was associated with elevated plasma TSH levels. Hepatic GSH levels were slightly depressed but there was no evidence of increased oxidative stress. A similar pattern of biochemical events has been observed to occur during dosed feed treatment with phenobarbital. These results suggest that oxazepam and phenobarbital may induce carcinogenesis by similar mechanisms in mice.
Griffin
R J
RJ
Chemistry Branch, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA.
Dudley
C N
CN
Cunningham
M L
ML
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D015786:Cytochromes b5 / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D005609:Free Radicals / Q000378:metabolism; D006993:Hypnotics and Sedatives / Q000378:metabolism / Q000633:toxicity*; D008099:Liver / Q000737:chemistry / Q000166:cytology / Q000187:drug effects*; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects; D009929:Organ Size / Q000187:drug effects; D010076:Oxazepam / Q000378:metabolism / Q000633:toxicity*; D010634:Phenobarbital / Q000378:metabolism / Q000633:toxicity*; D013438:Sulfhydryl Compounds / Q000378:metabolism; D013972:Thyrotropin / Q000097:blood / Q000187:drug effects*
D005609:Free Radicals; D006993:Hypnotics and Sedatives; D013438:Sulfhydryl Compounds; D010076:Oxazepam; D013972:Thyrotropin; D015786:Cytochromes b5; D003577:Cytochrome P-450 Enzyme System; D010634:Phenobarbital