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)retinamide (4-HPR) are effective chemopreventive agents against epithelial tumors in the oral cavity, breast, and prostate. We tested the inhibitory activity of these retinoids against N-nitrosomethylbenzylamine (NMBA)-induced tumorigenesis in the rat esophagus.


METHODS
Male Fischer 344 rats were randomly assigned 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 studied to investigate the mechanisms by which dietary 4-HPR affects tumorigenesis. All statistical tests were two-sided.


RESULTS
Dietary 4-HPR resulted in a dose-dependent and statistically significant enhancement (P<.05) of tumorigenesis in response to NMBA. In two different tumor bioassays, the mean tumor multiplicity for rats fed the highest concentration of dietary 4-HPR (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 lacking 4-HPR. Animals fed diets containing 9-cis-RA displayed no statistically significant increase in tumorigenesis. Compared with animals fed a diet lacking 4-HPR, animals fed 4-HPR had increased NMBA metabolism in esophageal explant cultures and had higher levels of O(6)-methylguanine DNA adducts and CYP2A3 mRNA in their esophagi.


CONCLUSIONS
Dietary 4-HPR enhances tumorigenesis in response to NMBA in the rat esophagus by increasing tumor initiation events. Dietary 4-HPR may exert paradoxical effects at some sites, such as the aerodigestive tract, by modulating the bioactivation of carcinogens in target tissues.
Gupta
A
A
Division of Environmental Health Sciences, The Ohio State University School of Public Health and Comprehensive Cancer Center, The Ohio State University, Columbus 43210, USA.
Nines
R
R
Rodrigo
K A
KA
Aziz
R A
RA
Carlton
P S
PS
Gray
D L
DL
Steele
V E
VE
Morse
M A
MA
Stoner
G D
GD
D000077556:Alitretinoin; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D002273:Carcinogens; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D018736:DNA Adducts; D004128:Dimethylnitrosamine / Q000031:analogs & derivatives / Q000378:metabolism*; D004938:Esophageal Neoplasms / Q000139:chemically induced / Q000188:drug therapy*; D004947:Esophagus / Q000187:drug effects; D017313:Fenretinide / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D012176:Retinoids / Q000627:therapeutic use; D013997:Time Factors; D014212:Tretinoin / Q000008:administration & dosage / Q000627:therapeutic use
D000970:Antineoplastic Agents; D002273:Carcinogens; D018736:DNA Adducts; D012333:RNA, Messenger; D012176:Retinoids; D017313:Fenretinide; D000077556:Alitretinoin; D014212:Tretinoin; D003577:Cytochrome P-450 Enzyme System; C014707:nitrosobenzylmethylamine; D004128:Dimethylnitrosamine