Part 1. The role of the intestinal tract in the elimination of carbon tetrachloride. Part 2. The effect of pyridine on xenobiotic metabolism in liver and lung

Donald A Page, Purdue University

Abstract

Part 1. Previous inhalation studies showed that a significant amount of unidentified ($\sp{14}$C) compound(s) appeared in the feces of rats and monkeys exposed to $\sp{14}\rm CCl\sb4.$ Fecal excretion by direct exsorption from the blood to the lumen of the intestinal tract is a major route of elimination for many lipophilic compounds that are resistant to metabolism. The purpose of this study was to determine the mechanism (biliary and/or nonbiliary) of fecal elimination of CCl$\sb4$ and/or its metabolite(s) in rats. The results indicate that both biliary and nonbiliary mechanisms contribute to the fecal elimination of CCl$\sb4$ following a single iv dose (1 mmol/kg), but this route accounts for less than 1% of the administered dose. The results also indicate that CCl$\sb4$ is not eliminated unchanged in the feces following either acute treatment (iv or ip) or repeated inhalation exposures. Direct exsorption of CCl$\sb4$ does not significantly contribute to the overall elimination of CCl$\sb4$. Part 2. Induction of specific isozymes of P450 can increase the metabolism of xenobiotics leading to increased detoxification or enhanced toxicity. This phenomenon is well characterized in the liver but less so in the lung. Pyridine is an effective inducer of the ethanol-inducible CYP2E1 in liver and lung. The purpose of this study was to determine the effect of pyridine on the hepatic and pulmonary metabolism and/or toxicity of 2-butanol, ethyl carbamate and bromobenzene, substrates whose hepatic metabolism and/or toxicity is altered by ethanol. Pyridine increased the in vitro hepatic metabolism of 2-butanol to methyl ethyl ketone and ethyl carbamate to CO$\sb2$. Pyridine decreased the in vitro pulmonary metabolism of 2-butanol but not ethyl carbamate. In vivo, pyridine decreased the bioactivation of ethyl carbamate and the hepatotoxicity of bromobenzene. The results indicate that pyridine-induced changes in xenobiotic metabolism are tissue specific, and that pyridine is an effective inducer of in vitro hepatic metabolism but can inhibit xenobiotic metabolism in vivo.

Degree

Ph.D.

Advisors

Carlson, Purdue University.

Subject Area

Pharmacology|Toxicology

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