Effect of experimental hepatic injury on in vitro drug-metabolizing enzyme activities in the rat
Willson, R.A.; Hart, F.E.
Gastroenterology 73(4 Pt 1): 691-696
1977
ISSN/ISBN: 0016-5085 PMID: 408219 Document Number: 111426
Experimental hepatic necrosis was induced in phenobarbital pretreated rats by i.p. administration of an acetaminophen-dimethyl sulfoxide mixture over a dosage range of 0.3-1.5 g/kg. At lower doses, cytochrome P-450 concentration and specific activities of aminopyrine demethylase and bilirubin glucuronyl transferase increased; aniline hydroxylase activity was mildly decreased. At higher doses cytochrome P-450 concentration and specific activities of all enzymes decreased significantly (P < 0.01) as compared with control rats. The diminished activities were generally modest, not uniform for all enzymes assayed and correlated poorly with histological necrosis and routine laboratory tests. When necrosis was severe a prominent peak was detected at 420 nm; this was associated with a more consequential decrease in all enzyme activities. When total in vitro hepatic drug-metabolizing enzyme capacity was calculated, only cytochrome P-450 content and aminopyrine demethylase activity were significantly decreased at the 1.5 g/kg dose level. In acute liver disease changes in the hepatic in vitro drug-metabolizing enzyme capacity may not be closely related to cellular necrosis. The degree of change in enzyme activities probably varies from 1 enzyme system to another. These findings may explain, in part, the often inconsistent alterations in the disposition and elimination of drugs described in associated liver diseases.