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James R, Desmond P, Kupfer A, Schenker S, Branch RA: The differential localization of various drug metabolizing systems within the rat liver lobule as determined by the hepatotoxins allyl alcohol, carbon tetrachloride and bromobenzene. J Pharmacol Exp Ther. 1981 Apr;217(1):127-32.
Rats were pretreated with allyl alcohol, carbon tetrachloride or bromobenzene to induce histopathological evidence of periportal, midzonal to centrilobular, and centrilobular hepatic necrosis. The amount of various drug metabolizing enzyme systems present after necrosis was determined indirectly by measuring the rate of metabolism for specific substrates in vitro. The chemically induced hepatocellular injury of these toxins produced variable but significant alterations in hepatic drug metabolism. The changes in enzymatic activity related well with the area of the lesion produced by each toxin. Thus, these hepatotoxins appear to be useful as probes to determine the hepatolobular distribution of the various drug metabolizing enzyme systems studied. Aniline hydroxylase and p-nitroanisole o-demethylase were concentrated in the midzonal and periportal zones, while aminopyrine N-demethylase was more uniformly distributed along the cytochrome P-450 gradient. Glucuronyltransferase was more heavily concentrated in the periportal-midzonal area, acetyltransferase was centrilobular-midzonal and glutathionetransferase was concentrated in the midzonal region. Thus, as is the case for cytochrome P-450, there appears to be a high degree of regional organization for all of the drug metabolizing enzymes within the hepatic lobule. |
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