Date of Award

1989

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

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

First Advisor

Wayne Flory

Abstract

The mechanism of action of 2-thiotriazone (TTZ) was evaluated in adult and immature rats of both sexes. TTZ produced marked pulmonary toxicity in rats that was both age and sex-dependent. It was highly toxic in male rats (oral LD50 of 4.6 mg/kg and ip LD50 of 1.4 mg/kg). Female rats were more resistant than males and immature rats (30-40 days of age) were totally resistant to TTZ toxicity. Gross and histological examination of lung tissue from rats exposed to TTZ showed severe pulmonary edema, effusion and mottling of the lungs. Significant increases in lung weights were also observed. Diethylmaleate (DEM) pretreatment potentiated the toxicity of TTZ in male, female, and immature rats, but L-buthionine-(SR)-sulfoxamine (BSO) did not affect TTZ toxicity. Lung weights in DEM-TTZ treated rats were twice as heavy as animals treated with TTZ alone. Resistance to TTZ could be produced in adult male rats by administration of a sublethal dose of TTZ (1mg/kg). Survival from a toxic dose also induced resistance which lasted up to 8 weeks in orally dosed rats and 6 weeks in ip dosed rats. $\beta$-Napthoflavone (BNF) induction of microsomal mixed function monooxygenase enzymes and N-acetyl-L-cysteine (NAC) produced resistance to TTZ in male rats. Diethylmaleate abolished both TTZ and BNF induced resistance to TTZ; however, BSO had no affect. Phenobarbital (PB) induction and treatment of rats with $\beta$-estradiol or testosterone did not affect TTZ toxicity. Also, toxicity could not be correlated with the stage of estrus. Cytochrome P-450 specific content was increased in female rats, and UDP-glucuronosyltransferase activity was decreased in both female and immature male rats treated with TTZ. Cytochrome P-450 specific content was described in male rats and PB induced male rats administered DEM-TTZ. All other specific contents and activities were unaffected. 2-Thiotriazone produced a dose-dependent decrease in lung glutathione (GSH) concentration in adult male rats. It also decreased GSH concentration in the lungs of female rats in a dose-independent manner. Diethylmaleate-TTZ depleted glutathione stores in the liver and lung of male and female rats. This study indicates that TTZ is probably metabolized to a short-lived reactive metabolite in the lungs by the cytochrome P-448 isozyme, although the involvement of the non-cytochrome containing flavin monooxygenase system can not be ruled out.

Pages

294

Share

COinS