DNA ADDUCT FORMATION BY TAMOXIFEN WITH RAT AND HUMAN LIVER MICROSOMALACTIVATION SYSTEMS

Using microsomal preparations from rat and human liver, we investigate d the activation of the anti-estrogen compound tamoxifen (TMX) to form DNA adducts. Pretreatment of rats with phenobarbital increased DNA ad duct formation by microsomal activation of TMX 3- to 6-fold, depending on the cofactors used. When reduced nicotinamide-adenine dinucleotide phosphate (NADPH) was used as a cofactor in human arid rat microsomal activation systems, the relative DNA adduct levels were 2.9 and 5.2 x 10(-8) respectively and 1-3 TMX-DNA adducts were detected by P-32-pos tlabeling; DNA adduct 1 was the same in both microsomal systems. When cumene hydroperoxide (CuOOH) was used as a cofactor, activation of TMX produced four major DNA adducts and several minor DNA adducts in both rat and human liver microsomes; the relative adduct levels were 11.1 and 23.1 x 10(-8) respectively. TMX-DNA adducts 1, 4, 5 and 6 were sim ilar in both human and rat microsomal systems with CuOOH as the cofact or. The TMX-DNA adducts formed with NADPH as the cofactor were clearly different from those formed with CuOOH as the cofactor, which implies that the metabolites leading to the individual DNA adducts were diffe rent. Addition of a P450 inhibitor, either n-octylamine or alpha-napth ylisothiocyanate, to the activation system reduced adduct formation by 70-93%. We propose that the TMX-DNA adducts formed with NADPH as the cofactor result from P450 acting as a mono-oxygenase, whereas the addu cts formed with CuOOH as the cofactor result from P450 acting as a per oxidase. Our findings suggest that further studies may be required to establish the safety of TMX treatment of women for purposes other than chemotherapy.