A 13-week toxicologic and pathologic evaluation of prolonged cytochromes P450 inhibition by 1-aminobenzotriazole in male rats.

The pharmacologic, toxicologic, and microscopic effects of 100 mg/kg/day of 1-Aminobenzotriazole (ABT), a suicide substrate inhibitor of cytochromes P450, were assessed in male Sprague-Dawley rats over a 13-week period. Hepatic cytochromes P450 levels and resorufin dealkylase activity were decreased to less than 30% of control values beginning at Day 2 and from Day 8 to Day 92. These decreases were not accompanied by overt clinical toxicity, e.g., changes in body weight, food consumption, or clinical appearance, during the study. Hemoglobin, hematocrit, and erythrocyte counts were slightly decreased at 8, 29, and 92 days and were accompanied by increased spleen weights and extramedullary hematopoiesis. Additionally, mean corpuscular hemoglobin concentration, mean corpuscular volume, red cell distribution width, and mean corpuscular hemoglobin were slightly increased at 92 days. Increases in liver weights at 8, 29, and 92 days were accompanied by centrilobular hypertrophy and intracytoplasmic vacuolization consistent with lipid accumulation. Thyroid stimulating hormone (TSH) was slightly elevated and triiodothyronine and thyroxine were slightly decreased at 29 days. TSH was also slightly elevated at 8 and 92 days, and thyroid gland weights were increased at 8, 29, and 92 days with microscopic evidence of hyperplasia and hypertrophy of thyroid gland follicular cells. Increased adrenal weights and hypertrophy of the zona fascicularis of the adrenal gland were observed at 8, 29, and 92 days. Kidney weights were also increased at these assessments. Changes in the thyroid gland, the thyroid hormone profile, and the liver may reflect increased synthesis of microsomal enzymes, an effect that is sometimes difficult to demonstrate directly with suicide substrate inhibitors of cytochromes P450. In general, 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 conditions.

Distribution of 1-aminobenzotriazole in male rats after administration of an oral dose.

1. 14C-labelled 1-aminobenzotriazole (ABT), a suicide inactivator of cytochrome P450, was synthesized and administered orally to male rats. The rats were killed at 1, 6, 24, 48 or 72 h after dosing and the concentration of total radioactivity in various tissues and organs measured. 2. The compound appears to be absorbed slowly with 50% of the radioactivity remaining in the stomach at 6 h after dosing and maximum plasma and tissue concentrations were observed at 24 h. 3. Approximately 71% of the dose of 14C was excreted in the urine and 12% in the faeces over 72 h, indicating oral absorption of at least 71%. Tissue-to-plasma ratios of 14C were highest in the liver, adrenals and kidneys, which all contain significant amounts of cytochrome P450; the half-lives of elimination for total 14C in liver, adrenals and kidneys were approximately 24, 16 and 12 h, respectively, while the half-life in plasma was approximately 9 h. 4. ABT was metabolized by N-acetylation, with the acetylated product attaining concentrations equal to ABT in the plasma; two other major metabolites were also excreted in the urine namely, the N-glucuronide of 1-aminobenzotriazole and the N-glucuronide of benzotriazole.

1-Aminobenzotriazole-induced destruction of hepatic and renal cytochromes P450 in male Sprague-Dawley rats.

1-Aminobenzotriazole (ABT) is a suicide substrate of both hepatic and pulmonary cytochromes P450. The present studies were designed to compare the effects of ABT on hepatic and renal metabolism. Hepatic and renal microsomes and cytosol were prepared from male Sprague-Dawley rats following ABT pretreatment (0-100 mg/kg ip) for various times. Administration of 100 mg ABT/kg produced profound reductions in P450 content in both liver and kidney within 2 hr; loss of P450 in both tissues persisted for at least 48 hours. ABT-induced destruction of P450 was dose-dependent. Maximal destruction of about 80% of total hepatic P450 occurred at dosages of ABT equal to or greater than 10 mg/kg. Maximal destruction of about 80% of total renal P450 occurred at dosages of ABT equal to or greater than 50 mg/kg. In vitro, ABT rapidly and efficiently destroyed P450 in both hepatic and renal microsomes prepared from naive male Sprague-Dawley rats. Incubation of hepatic or renal microsomes in vitro with ABT produced detectable destruction of P450 within 5 min. Maximal destruction of P450 occurred within 10 min in both hepatic and renal microsomes during in vitro incubation with ABT. ABT-induced destruction of P450 in vitro was concentration-dependent. For hepatic microsomes, maximal destruction of about 70% of P450 required concentrations of ABT equal to or greater than 10 mM. For renal microsomes, maximal destruction of about 80% of P450 required concentrations of ABT equal to or greater than 10 mM. In both liver and kidney, only P450 content and P450-dependent activities were significantly decreased.(ABSTRACT TRUNCATED AT 250 WORDS)