Effects of dietary N-(4-hydroxyphenyl)retinamide on N-nitrosomethylbenzylamine metabolism and esophageal tumorigenesis in the Fischer 344 rat

Background: 9-cis-Retinoic acid (9-cis-RA) and N-(4-hydroxyphenyl)retinamid e (4-HPR) are effective chemopreventive. agents against epithelial tumors i n the oral cavity, breast,and prostate. We tested the inhibitory activity o f these retinoids against N-nitrosomethylbenzylamine (NMBA)-induced tumorig enesis in the rat esophagus, Methods: Male Fischer 344 rats were randomly a ssigned to receive diets either lacking or containing 9-cis-RA or 4-HPR for 1 week before tumor initiation with NMBA and then for the duration of the study. NMBA metabolism, O-6-methylguanine adduct formation, and cytochrome P450 messenger RNA (mRNA) expression in the esophagi of the rats were studi ed to investigate the mechanisms by which dietary 4-HPR affects tumorigenes is. All statistical tests were two-sided. Results: Dietary 4-HPR resulted i n a dose-dependent and statistically significant enhancement (P < .05) of t umorigenesis in response to NMBA, In two different tumor bioassays, the mea n tumor multiplicity for rats fed the highest concentration of dietary 4-HP R (0.8 g/kg diet) was increased by 5.9 tumors (95% confidence interval [CI] = 1.7 to 10.1 tumors) and 6.7 tumors (95% CI = 5.6 to 7.8 tumors) compared with the mean tumor multiplicity for rats that received the control diet l acking 4-HPR. Animals fed diets containing 9-cis-RA displayed no statistica lly significant increase in tumorigenesis, Compared with animals fed a diet lacking 4-HPR; animals fed 4-HPR had increased NMBA metabolism in esophage al explant cultures and had higher levels of O-6-methylguanine DNA adducts and CYP2A3 mRNA in their esophagi. Conclusions: Dietary 4-HPR enhances tumo rigenesis in response to NMBA in the rat esophagus by increasing tumor init iation events. Dietary 4-HPR may exert paradoxical effects at some sites, s uch as the aerodigestive tract, by modulating the bioactivation of carcinog ens in target tissues.