title: BMS-189453, a novel retinoid receptor antagonist, is a potent testicular toxin.
abstract: BMS-189453 is a synthetic retinoid that acts as an antagonist at retinoic acid receptors alpha, beta, 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.
authors.affiliation: Drug Safety Evaluation, Bristol-Myers Squibb Pharmaceutical Research Institute, Syracuse, NY 13221-4755, USA. gene.schulze@bms.com
authors.forename: G E
authors.initials: GE
authors.lastname: Schulze
authors.forename: R J
authors.initials: RJ
authors.lastname: Clay
authors.forename: L E
authors.initials: LE
authors.lastname: Mezza
authors.forename: C L
authors.initials: CL
authors.lastname: Bregman
authors.forename: R A
authors.initials: RA
authors.lastname: Buroker
authors.forename: J D
authors.initials: JD
authors.lastname: Frantz
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000469:Alkaline Phosphatase / Q000097:blood; D000818:Animals; D001284:Atrophy; D001835:Body Weight / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects; D008297:Male; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects; D009929:Organ Size / Q000187:drug effects; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D018168:Receptors, Retinoic Acid / Q000037:antagonists & inhibitors*; D012176:Retinoids / Q000633:toxicity*; D013045:Species Specificity; D013076:Sperm Count; D013737:Testis / Q000187:drug effects* / Q000473:pathology; D013997:Time Factors
chemical_list: C423184:BMS 189453; D018168:Receptors, Retinoic Acid; D012176:Retinoids; D000410:Alanine Transaminase; D000469:Alkaline Phosphatase