EFFECT OF TAMOXIFEN FEEDING ON METABOLIC-ACTIVATION OF TAMOXIFEN BY THE LIVER OF THE RHESUS-MONKEY - DOES LIVER ACCUMULATION OF INHIBITORY METABOLITES PROTECT FROM TAMOXIFEN-DEPENDENT GENOTOXICITY AND CANCER

Tamoxifen induces hepatocellular carcinomas in rats and is converted b y rat hepatic cytochrome P450 enzymes into reactive metabolites capabl e of forming adducts with nucleic acids, proteins and chromosomal aber rations, In rats tamoxifen has also been shown to induce liver cytochr ome P450 enzymes, to stimulate its own metabolism leading to greater c ovalent binding and to induce a higher degree of unscheduled DNA synth esis, This suggests that, at least in the rat, a sensitive species, ta moxifen may contribute significantly to its genotoxic and carcinogenic potential, by assisting its own metabolic activation, We have now inv estigated the effect of feeding tamoxifen to male and female Rhesus mo nkeys, A marked induction of the hepatic cytochrome(s) P450 is found i n the monkey but, in spite of this, the in vitro metabolism of 7-ethox yresorufin by microsomes from treated animals is markedly inhibited an d so is the dealkylation of two other 7-alkoxyresorufin substrates. Ev idence is presented for the accumulation in the liver of monkeys treat ed,vith tamoxifen of a powerful inhibitor of drug metabolism, and the inhibitor is identified as a metabolite of tamoxifen, its N,N-didesmet hyl derivative, The level of P-32-postlabelled DNA adducts was conside rably higher in rats given tamoxifen than in similarly treated monkeys , Also, whereas rats responded to tamoxifen treatment with a marked in crease in covalent binding to microsomal protein, in the monkeys, wher e accumulation of the inhibitory metabolite in the microsomal fraction was also seen, covalent binding was not greater with microsomes from treated animals than in the corresponding controls, N,N-Didesmethyl-ta moxifen, added in vitro to human and rat microsomes, reduced significa ntly the extent of covalent binding, suggesting that the accumulation of the metabolite observed in the liver of primates may discourage the cytochrome P450-dependent conversion of tamoxifen into reactive deriv atives and in this way protect against the formation of adducts, This mechanism may also contribute to protecting the primate against tamoxi fen-induced liver cancer.