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.
Meschter
C L
CL
Department of Toxicology, Hoffmann-LaRoche, Nutley, New Jersey 07110.
Mico
B A
BA
Mortillo
M
M
Feldman
D
D
Garland
W A
WA
Riley
J A
JA
Kaufman
L S
LS
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D019363:Cytochrome P-450 CYP1A1; D065607:Cytochrome P-450 Enzyme Inhibitors; D004435:Eating / Q000187:drug effects; D008099:Liver / Q000473:pathology; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000648:ultrastructure; D009929:Organ Size / Q000187:drug effects; D010088:Oxidoreductases / Q000037:antagonists & inhibitors; D051381:Rats; D011919:Rats, Inbred Strains; D014230:Triazoles / Q000097:blood / Q000633:toxicity*
D065607:Cytochrome P-450 Enzyme Inhibitors; D014230:Triazoles; C033020:1-aminobenzotriazole; D010088:Oxidoreductases; D019363:Cytochrome P-450 CYP1A1