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Toxicological Sciences 59, 297-308 (2001)
Copyright © 2001 by the Society of Toxicology

REPRODUCTIVE AND DEVELOPMENTAL TOXICOLOGY

BMS-189453, a Novel Retinoid Receptor Antagonist, Is a Potent Testicular Toxin

Gene E. Schulze1, Richard J. Clay, Lawrence E. Mezza, Carla L. Bregman, Robert A. Buroker and Jerry D. Frantz

Drug Safety Evaluation, Bristol-Myers Squibb Pharmaceutical Research Institute, Syracuse, New York

BMS-189453 is a synthetic retinoid that acts as an antagonist at retinoic acid receptors {alpha}, ß, and {gamma}. In Sprague Dawley rats at daily oral doses of 15, 60, or 240 mg/kg for 1 month, BMS-189453 produced increases in leukocyte counts, alkaline phosphatase and alanine aminotransferase levels, and marked testicular degeneration and atrophy at all doses. Significant overt signs of toxicity and deaths occurred at 240 mg/kg, whereas body-weight and food-consumption decreases occurred at 60 and 240 mg/kg. When BMS-189453 was administered to male rats at daily doses ranging from 12.5 to 100 mg/kg for 1 week, only minimal testicular changes occurred at all doses, shortly after the dosing period. However, after a 1-month drug-free observation period, marked testicular atrophy was evident at all doses. BMS-189453 was then administered at doses of 2, 10, or 50 mg/kg to male rats for 1, 3, or 7 consecutive days. Dose- and duration-dependent testicular toxicity that occurred after a 1-month observation period did not recover, and, in some cases, was more severe 4 months after the last dose. In rabbits administered BMS-189453 at oral doses of 2, 10, or 50 mg/kg for 1 week, testicular degeneration and atrophy were evident in the high-dose group at 1 month following treatment. These studies indicate that retinoid antagonists can selectively produce progressive and prolonged testicular toxicity after single or repeated oral doses that are otherwise well tolerated.

Key Words: retinoic acid receptor antagonist; testicular toxicity; rats; rabbits; toxicity; retinoids; Vitamin A; oral; in vivo; safety assessment.


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