INHIBITION BY N-(4-HYDROXYPHENYL)RETINAMIDE AND ALL-TRANS-RETINOIC ACID OF EXOGENOUS AND ENDOGENOUS DEVELOPMENT OF PUTATIVE PRENEOPLASTIC, GLUTATHIONE-S-TRANSFERASE PLACENTAL FORM-POSITIVE LESIONS IN THE LIVERS OF RATS

The effects of N-(4-hydroxyphenyl)retinamide (4-HPR) and all-trans-ret inoic acid (tRA) on the exogenous and endogenous models of rat liver c arcinogenesis respectively using diethylnitrosamine (DEN) and a cholin e-deficient, L-amino acid-defined (CDAA) diet were studied, For the ex ogenous study, male Fischer 344 rats, 6 weeks old, were given a single i.p. dose of 200 mg/kg body wt of DEN, partially hepatectomized at we ek 3, administered 4-HPR at doses of 0, 0.04, 0.08 and 0.16% or tRA at 0, 0.004, 0.008 and 0.015% in diet from week 2 for 6 weeks, and kille d at the end of week 8, For the endogenous study, rats were fed the CD AA diet containing 4-HPR or tRA for 12 weeks and killed at the end of week 12, 4-HPR decreased the numbers and sizes of the glutathione S-tr ansferase placental form-positive foci, assayed as putative preneoplas tic lesions, the levels of 8-hydroxyguanine (8-OHG), a parameter of ox idative DNA damage, and the bromodeoxyuridine labeling indices (BrdU L .I.) by all three doses in the DEN-initiated case and, more prominentl y, in the CDAA diet-associated case, In contrast, while tRA failed to exert inhibitory effects apparently on foci development, 8-OHG formati on or BrdU labeling in the DEN-initiated case, it reduced the numbers and sizes of the foci, the 8-OHG levels and the BrdU L.I. by all three doses in the CDAA diet-associated case, Furthermore, both 4-HPR and t RA inhibited the CDAA diet-associated induction of hepatocyte necrosis and connective tissue increase but not intrahepato-cellular fat accum ulation, These results indicate that 4-HPR exerts chemopreventive effe cts against the exogenous and endogenous rat liver carcinogenesis, whi le tRA can inhibit only the latter.