Date of Award

1990

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Veterinary Physiology, Pharmacology, and Toxicology (Veterinary Medical Sciences)

First Advisor

Wayne Flory

Second Advisor

Charles Short

Abstract

The effect of an extract of Sesbania drummondii on the hepatic cytochrome P-450 monooxygenase system was evaluated in two experimental models, the White Leghorn chicken and the Sprague-Dawley rat. The cytochrome P-450 monooxygenase systems were compared using studies of catalytic activities and two major enzyme components, cytochrome P-450 and NADPH-cytochrome P-450 reductase. Two "classical" cytochrome P-450 inducers, phenobarbital and $\beta$-naphthoflavone, were used to probe induction mechanisms. S. drummondii induced opposite effects on the hepatic cytochrome P-450 component of chickens versus rats. Cytochrome P-450 specific content was increased 2-fold in chickens but decreased 2-fold in rats. Qualitative differences in microsomal proteins were found using SDS-gel electrophoresis. The protein profile of S. drummondii-treated chickens was induced differently from phenobarbital or $\beta$-naphthoflavone. In the rat, the microsomal protein profile was similar to controls but of lower protein band staining intensity. Western blots revealed two S. drummondii-induced microsomal proteins of chickens that cross-reacted with antibody against rat P-450IA1. One of these proteins corresponded to the $\beta$-naphthoflavone-induced chicken protein. The other appeared unique to S. drummondii treatment. Neither of protein was detected by this antibody in the S. drummondii-treated rat. Sesbania drummondii induced different responses in chicken versus rat cytochrome P-450 catalytic activities. Chickens showed increases of 2-fold in aminopyrine N-demethylase and 4-fold in aldrin epoxidase; no change in ethoxyphenoxazone and benzyloxyphenoxzone O-dealkylases; and a 2-fold decrease in pentoxyphenoxazone O-dealkylase. Similar activities were induced by phenobarbital. In contrast, S. drummondii-treated rats had 2 to 3-fold decreases in all activities, except ethoxyphenoxazone O-dealkylase, which was unchanged. Species differences were also observed in the effect of S. drummondii on the NADPH-cytochrome P-450 reductase component. S. drummondii-treatment induced a 2-fold increase in NADPH-cytochrome c reductase activity in chickens but no change in treated rats. Use of cumene hydroperoxide indicated that the induced effects on the reductase contribute to aminopyrine but not aldrin metabolism in the chicken, and neither substrate metabolism in the rat. These findings suggest that Sesbania drummondii can induce changes in hepatic cytochrome P-450 monooxygenase systems and these changes are species-dependent.

Pages

305

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