Effects of brotizolam on mixed-function oxidases and glutathione metabolism in the rat

Xenobiotica; the Fate of Foreign Compounds in Biological Systems
S TongD V Parke

Abstract

Intra-gastric administration of brotizolam (0.1-200 mg/kg) daily for three days to rats resulted in no significant changes in the hepatic and intestinal cytochrome P-450-dependent or P-448-dependent mixed-function oxidases, or in the hepatic flavoprotein dimethylaniline N-oxidase. Liver microsomes from mouse, rat and man metabolized brotizolam by hydroxylation of the diazepine ring and of the methyl group at rates which were greater for mouse greater than rat greater than man. Brotizolam and its metabolites generated by rat-liver microsomes in vitro were not mutagenic in the Ames' test. Brotizolam, at 200 mg/kg per day for two to six weeks, depleted liver glutathione concentration and markedly increased liver gamma-glutamyl transpeptidase, glutathione reductase and glutathione transferase activities. Similar changes were not seen at the lower dose of 0.3 mg/kg. The observed increases in glutathione metabolism and the decreased tissue concentration of glutathione are indicative of high levels of glutathione conjugation, and provide a possible explanation for the equivocal increase in tumorigenicity seen in rats receiving brotizolam at high dosage.

References

Oct 1, 1975·The Journal of Pharmacy and Pharmacology·C Ioannides, D V Parke
Jan 1, 1979·Environmental Mutagenesis·M J PrivalA T Sheldon
Oct 1, 1974·Clinical Pharmacology and Therapeutics·J R MitchellH Keiser
Jul 1, 1984·The Biochemical Journal·C E PhillipsonD V Parke
Jan 1, 1983·British Journal of Clinical Pharmacology·F J KuhnK Stockhaus
May 1, 1983·Mutation Research·D M Maron, B N Ames
Jan 1, 1984·Archives of Toxicology. Supplement. = Archiv Für Toxikologie. Supplement·D V Parke, C Ioannides
Aug 1, 1983·Biochemical Society Transactions·D V Parke
Jan 1, 1983·British Journal of Clinical Pharmacology·W D Bechtel
Jan 1, 1983·British Journal of Clinical Pharmacology·A N Nicholson
Jan 1, 1983·British Journal of Clinical Pharmacology·C HewettH Stötzer
Jan 1, 1984·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·C IoannidesD V Parke
Jan 1, 1982·Carcinogenesis·M K LoganiT J Slaga
Jan 1, 1981·Advances in Experimental Medicine and Biology·D V Parke, C Ioannides
Mar 9, 1964·Biochemical and Biophysical Research Communications·D M Ziegler, F H Pettit

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Citations

Dec 1, 1986·Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association·D H MonroeD L Eaton

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