STRONG EVIDENCE FROM STUDIES WITH BRACHYMORPHIC MICE AND PENTACHLOROPHENOL THAT 1'-SULFOOXYSAFROLE IS THE MAJOR ULTIMATE ELECTROPHILIC AND CARCINOGENIC METABOLITE OF 1'-HYDROXYSAFROLE IN MOUSE-LIVER

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  • 1 January 1983
    • journal article
    • research article
    • Vol. 43  (11) , 5163-5173
Abstract
The role of sulfation of 1''-hydroxysafrole in the formation of hepatic macromolecular adducts and in heaptic tumor formation in mice given 1''-hydroxysafrole was investigated by the use of: mice treated with the specific sulfotransferase inhibitor pentachlorophenol; and brachymorphic mice, which are characterized by a deficiency in the hepatic synthesis of 3''-phosphoadenosine 5''-phosphosulfate. Cytosolic sulfotransferase activity for 1''-hydroxysafrole in mouse and rat liver was significantly inhibited by 10 .mu.M pentachlorophenol, usually by > 90%. Prior administration of nontoxic amounts of pentachlorophenol, in the diet of adult female CD-1 mice or by i.p injection of 12-day-old male C57BL/6 .times. C3H F1 (hereafter called B6C3F1) mice, resulted in an 85% decrease in the level of adducts formed from 1''-hydroxysafrole in hepatic DNA and RNA. Chronic administration of a nontoxic level of pentachlorophenol in the diet of adult female CD-1 mice strongly inhibited hepatic tumor induction by long-term dietary administration of safrole or 1''-hydroxysafrole. Initiation of hepatic tumors by a single i.p. injection of 1''-hydroxysafrole to 12-day-old male B6C3F1 mice was strongly inhibited by prior treatment with pentachlorophenol. Supplementation with ATP and sulfate of hepatic cytosols from adult female or 12-day-old brachymorphic progeny of a B6C3 background outbred to B6C3F1 mice (B6C3F2), of either sex, resulted in 5- to 10-fold less binding of 1''-hydroxysafrole to added RNA than when cytosols from phenotypically normal B6C3F2 mice were used. On administration of [3H]-1''-hydroxysafrole to adult female or 12-day-old brachymorphic B6C3F2 mice of either sex, the levels of hepatic DNA and RNA adducts were 7- to 12-fold lower than those obtained in phenotypically normal B6C3F2 mice of the same age and sex. Brachymorphic mice were also much less responsive than their phenotypically normal littermates to the induction of liver tumors by 1''-hydroxysafrole; lower incidences were observed both when the carcinogen was fed chronically to adult females and when it was administered to males only prior to weaning. These data strongly support the conclusion that 1''-sulfoxysafrole is the major ultimate electrophilic and tumor-initiating metabolite of 1''-hydroxysafrole.

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