A 13-WEEK TOXICOLOGIC AND PATHOLOGICAL EVALUATION OF PROLONGED CYTOCHROMES P450 INHIBITION BY 1-AMINOBENZOTRIAZOLE IN MALE-RATS

The pharmacologic, toxicologic, and microscopic effects of 100 mg/kg/d ay of 1-Aminobenzotriazole (ABT), a suicide substrate inhibitor of cyt ochromes P450, were assessed in male Sprague-Dawley rats over a 13-wee k period. Hepatic cytochromes P450 levels and resorufin dealkylase act ivity were decreased to less than 30% of control values beginning at D ay 2 and from Day 8 to Day 92. These decreases were not accompanied by overt clinical toxicity, e.g., changes in body weight, food consumpti on, or clinical appearance, during the study. Hemoglobin, hematocrit, and erythrocyte counts were slightly decreased at 8, 29, and 92 days a nd were accompanied by increased spleen weights and extramedullary hem atopoiesis. Additionally, mean corpuscular hemoglobin concentration, m ean corpuscular volume, red cell distribution width, and mean corpuscu lar hemoglobin were slightly increased at 92 days. Increases in liver weights at 8, 29, and 92 days were accompanied by centrilobular hypert rophy and intracytoplasmic vacuolization consistant with lipid accumul ation. Thyroid stimulating hormone (TSH) was slightly elevated and tri iodothyronine and thyroxine were slightly decreased at 29 days. TSH wa s also slightly elevated at 8 and 92 days, and thyroid gland weights w ere increased at 8, 29, and 92 days with microscopic evidence of hyper plasia and hypertrophy of thyroid gland follicular cells. Increased ad renal weights and hypertrophy of the zona fascicularis of the adrenal gland were observed at 8, 29, and 92 days. Kidney weights were also in creased at these assessments. Changes in the thyroid gland, the thyroi d hormone profile, and the liver may reflect increased synthesis of mi crosomal enzymes, an effect that is sometimes difficult to demonstrate directly with suicide substrate inhibitors of cytochromes P450. In ge neral, the effects of daily ABT administration to male rats at a dose that significantly reduces oxidative metabolism over a 13-week period were considered to be well-tolerated under controlled laboratory condi tions. (C) 1994 Society of Toxicology.