alpha-Naphthylisothiocyanate induced alterations in hepatic drug metabolizing enzymes and liver morphology: implications concerning anticarcinogenesis.
Alpha-naphthylisothiocyanate (ANIT) is a biliary toxin with anticarcinogenic properties. The studies described were designed to investigate the effects of continuous ANIT feeding on liver function. Male F-344 rats were fed ANIT at 0.01%, 0.022%, 0.047%, and 0.1% of the diet for 2, 4, and 6 weeks. Microscopic evaluation of liver sections revealed time- and dose- dependent bile duct proliferation, bile duct cell hypertrophy, and focal hepatocytic necrosis. Liver derived serum enzyme activity and serum bilirubin concentrations were increased in a fashion which correlated closely with the histological observations. A dose dependent decrease in hepatic cytochrome P-450 content, ethoxycoumarin-O-deethylase activity, and benzphetamine-N-demethylase activity was observed after 2 and 4 weeks of feeding ANIT. However, these enzyme activities returned to control values at 6 weeks in all except the 0.1% group. ANIT increased microsomal epoxide hydrolase and cytosolic DT-diaphorase activity (200-6005 of control). The enhancement was dose related and peaked at 2 and 4 weeks for epoxide hydrolase and DT-diaphorase, respectively. Both epoxide hydrolase and DT-diaphorase activity remained elevated at 6 weeks. These results suggest that ANIT mediated anticarcinogenesis, previously hypothesized to be the result of reduced mixed function oxidase activity, also may be accounted for by enhanced epoxide hydrolase and DT-diaphorase activity.
D015058:1-Naphthylisothiocyanate / Q000633:toxicity*; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001663:Bilirubin / Q000097:blood; D001835:Body Weight / Q000187:drug effects; D002273:Carcinogens / Q000037:antagonists & inhibitors*; D003135:Common Bile Duct / Q000502:physiology; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008297:Male; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D013861:Thiocyanates / Q000633:toxicity*
D002273:Carcinogens; D004364:Pharmaceutical Preparations; D013861:Thiocyanates; D015058:1-Naphthylisothiocyanate; D000410:Alanine Transaminase; D001663:Bilirubin