Hamster exhibits major differences in organ-specific metabolism of the esophageal carcinogen N-nitrosodiethylamine.
Nitrosamines are carcinogens that require metabolic activation by CYP enzymes in order to exert their carcinogenic effect. Species differences exist in their esophageal carcinogenic potency, with the rat being the most sensitive and the Syrian hamster a resistant species. In the latter, the liver is the main target organ. This difference does not apply to directly acting N-nitroso compounds, suggesting that tissue-specific metabolic activation is involved in hamster esophageal resistance to nitrosamines. We have previously shown that Cytochrome P450 2A3 (CYP2A3) is responsible for N-nitrosodiethylamine activation in the rat esophagus. In order to find a mechanistic explanation for the resistance of hamster esophagus for nitrosamines, we have compared the metabolism of NDEA between esophagus and liver of the hamster. Hamster esophagus is capable of activating NDEA (K(m)=1.02+/-0.44microM and V(max)=1.96+/-0.26nmol acetaldehyde/min/mg microsomal protein). However, the hamster liver showed a 40-fold higher catalytic efficiency (V(max)/K(m)) towards NDEA metabolism compared with its esophagus. Hamster esophagus expresses CYP2A8, CYP2A9 and CYP2A16, but not CYP2E1. An antibody against human CYP2A6 was able to inhibit NDEA metabolism in hamster esophageal, but not liver microsomes. Our results suggest that in the hamster esophagus, but not in the liver, most of the NDEA is metabolized by CYP2A enzymes, but with a rather poor efficiency when compared to the liver. This is in accordance with previous results showing that for the hamster, the main target organ of NDEA is the liver.
Visoni
Sílvia
S
Laboratório de Toxicologia e Biologia Molecular, Departamento de Bioquímica, Instituto de Biologia Roberto Alcântara Gomes, Universidade do Estado do Rio de Janeiro (UERJ), Rio de Janeiro, RJ, Brazil.
Lang
Matti
M
Ribeiro Pinto
Luis Felipe
LF
D000477:Alkylating Agents / Q000378:metabolism / Q000633:toxicity; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D002273:Carcinogens / Q000378:metabolism* / Q000633:toxicity; D006224:Cricetinae; D065637:Cytochrome P-450 CYP2A6; D004052:Diethylnitrosamine / Q000378:metabolism* / Q000633:toxicity; D004938:Esophageal Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D004947:Esophagus / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008647:Mesocricetus; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D009602:Nitrosamines / Q000378:metabolism / Q000633:toxicity; D009928:Organ Specificity; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000477:Alkylating Agents; D002273:Carcinogens; D009602:Nitrosamines; D004052:Diethylnitrosamine; D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; D065637:Cytochrome P-450 CYP2A6