Carcinogenic and mutagenic activities of safrole, 1'-hydroxysafrole, and some known or possible metabolites.

Abstract

The carcinogenic and mutagenic activities of metabolites and possible metabolites of safrole and 1′-hydroxysafrole were investigated as guides to their importance as possible proximate or ultimate carcinogens. 1′-Acetoxysafrole and the 2′,3′-oxides of safrole, 1′-hydroxysafrole, 1′-acetoxysafrole, and 1′-oxosafrole, were directly mutagenic for Salmonella typhimurium strains TA1535 and TA100. No significant mutagenicity was detected with safrole, isosafrole, 2′,3′-dihydrosafrole, 1′-hydroxysafrole, 3′-hydroxyisosafrole, 3′-acetoxyisosafrole, or 1′-oxosafrole either with or without the addition of reduced nicotinamide adenine dinucleotide phosphate-fortified hepatic microsomes plus cytosol. Multiple topical applications to mice of 1′-hydroxysafrole-2′,3′-oxide, followed by repetitive doses of croton oil, caused the formation of skin papillomas. Under the same conditions significant numbers of papillomas were not initiated by safrole, 1′-acetoxysafrole, 1′-hydroxysafrole, 1′-oxosafrole, safrole-2′,3′-oxide, or 1′-acetoxysafrole-2′,3′-oxide. 1′-Oxosafrole had little or no carcinogenic activity on p.o. administration to rats or on s.c. administration to preweanling mice or adult rats. The incidence of hepatocellular carcinomas in rats fed safrole was markedly increased by simultaneous administration of phenobarbital. 1′-Hydroxysafrole p.o. was more hepatotoxic and hepatocarcinogenic for adult female mice than for adult male mice. Injection of [2′,3′-3H]-1′-hydroxysafrole i.p. yielded at least 10-fold greater levels of hepatic DNA-, ribosomal RNA-, and protein-bound derivatives in preweanling male of female mice and in adult female mice than in adult male mice. The levels of hepatic macromolecule-bound tritiated derivatives in adult mice were produced by prefeeding of nonradioactive 1′-hydroxysafrole prior to the administration of [3H]-1′-hydroxysafrole. Multiple electrophiles, especially safrole-1′-sulfate, 1′-hydroxysafrole-2′,3′-oxide, 1′-oxosafrole, and safrole-2′,3′-oxide, must be considered as possible ultimate carcinogenic metabolites of safrole in mouse and rat liver.