The side-chain epoxidation and hydroxylation of the hepatocarcinogens safrole and estragole and some related compounds by rat and mouse liver microsomes.

Safrole, estragole, and their 2',3'-oxides were hydroxylated by hepatic microsomes from rats and mice at the 1'-carbon; trans-anethole was hydroxylated at the 3'-carbon; and safrole, estragole, and their 1'-hydroxy derivatives were epoxidized at the 2',3'-double bond. The 2',3'-epoxidation of eugenol was just detectable. The formation of these metabolites was dependent on an NADPH-generating system and on cytochrome P-450. In the absence of 3,3,3-trichloropropylene oxide little or no safrole-, estragole-, or eugenol-2',3'-oxide was recovered when these oxides were added to the incubations; recoveries of 50-70% were obtained in its presence. The recoveries of the 2',3'-oxides of 1'-hydroxy-safrole and of 1'-hydroxyestragole were 50-80% in the absence of trichloropropylene oxide and nearly quantitative in its presence. All incubations for analysis of epoxidation rates contained trichloropropylene oxide. The rates of metabolite formation ranged from about 0.4 nmol of eugenol-2',3'-oxide/mg protein/h by female rat liver microsomes to about 270 nmol of trans-3'-hydroxyanethole/mg protein/h for male rat liver microsomes. The rates of epoxidation and hydroxylation were greater for the estragole derivatives than for the safrole derivatives. The rates of epoxidation of safrole and estragole were greater than for their 1'-hydroxy derivatives.