Dn. Pathak et Wj. Bodell, DNA ADDUCT FORMATION BY TAMOXIFEN WITH RAT AND HUMAN LIVER MICROSOMALACTIVATION SYSTEMS, Carcinogenesis, 15(3), 1994, pp. 529-532
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.