Characterization of the biliary and urinary glutathione and N-acetylcysteine metabolites of the hepatic carcinogen 1'-hydroxysafrole and its 1'-oxo metabolite in rats and mice.
The hepatocarcinogen safrole is metabolized both to 1'-hydroxysafrole, a proximate hepatocarcinogen, and to 1'-oxosafrole, which is electrophilic but has little or no carcinogenic activity in rats and mice. As a part of a study on the metabolic interrelationships of these metabolites, their biliary and urinary conjugates were investigated. Administration of a single i.p. dose of [2',3'-3H]-1'-oxosafrole to male Sprague-Dawley rats or female CD-1 mice with cannulated bile ducts resulted in the excretion of 2 major biliary metabolites. These metabolites were isolated by high-performance liquid chromatography and characterized by 1H-nuclear magnetic resonance spectroscopy as 3'-(glutathion-S-yl)-1'-oxo-2',3'-dihydrosafrole and 3'-(N-acetylcystein-S-yl)-1'-oxo-2',3'-dihydrosafrole. The latter conjugate was also found in the urine. These conjugates were synthesized by non-enzymatic reaction of 1'-oxosafrole with glutathione and N-acetylcysteine at pH 8. After a single i.p. dose of [2',3'-3H]-1'-hydroxysafrole, the major biliary and urinary metabolite in rats was the glucuronide of this alcohol. Lower levels of the glutathione and N-acetylcysteine conjugates of 1'-oxosafrole appeared in the bile, and the latter conjugate was also found in the urine. Similar findings were made on the biliary metabolites of 1'-hydroxysafrole in mice. Although the sulfuric acid ester of 1'-hydroxysafrole is the major metabolite leading to the formation of DNA adducts in the liver, it was, at most, of minor importance in the formation of glutathione adducts. Only a very small percentage of a dose of 1'-hydroxysafrole was excreted in the bile of rats or mice as products that cochromatographed with 1'-(glutathion-S-yl)-safrole and 3'-(glutathion-S-yl)-isosafrole; no 3'-(N-acetylcystein-S-yl)-isosafrole was detected. These latter conjugates were synthesized by nonenzymatic reactions at pH 8.5 of the model electrophilic ester 1'-acetoxysafrole with glutathione or N-acetylcysteine.
D000111:Acetylcysteine / Q000378:metabolism* / Q000652:urine; D000818:Animals; D001646:Bile / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D004149:Dioxoles / Q000378:metabolism*; D005260:Female; D005978:Glutathione / Q000378:metabolism* / Q000652:urine; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D051381:Rats; D011919:Rats, Inbred Strains; D012451:Safrole / Q000031:analogs & derivatives / Q000378:metabolism*; D013053:Spectrophotometry
D004149:Dioxoles; C042314:1'-oxosafrole; C012376:1'-hydroxysafrole; D005978:Glutathione; D012451:Safrole; D000111:Acetylcysteine