Abstract:
: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.
journal_name
Cancer Resjournal_title
Cancer researchauthors
Fennell TR,Miller JA,Miller ECsubject
Has Abstractpub_date
1984-08-01 00:00:00pages
3231-40issue
8eissn
0008-5472issn
1538-7445journal_volume
44pub_type
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