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Title: Translational research into species differences of endocrine toxicity via steroidogenesis inhibition by SMP-028 — For human safety in clinical study

SMP-028 is a drug candidate developed for the treatment of asthma. In a 13-week repeated dose toxicity study of SMP-028 in rats and monkeys, differences of endocrine toxicological events between rats and monkeys were observed. In rats, these toxicological events mainly consisted of pathological changes in the adrenal, testis, ovary, and the other endocrine-related organs. On the other hand, in monkeys, no toxicological events were observed. The goal of this study is to try to understand the reason why only rats, but not monkeys, showed toxicological events following treatment with SMP-028 and to eventually predict the possible toxicological effect of this compound on human endocrine organs. Our results show that SMP-028 inhibits neutral cholesterol esterase more strongly than other steroidogenic enzymes in rats. Although SMP-028 also inhibits monkeys and human neutral cholesterol esterase, this inhibition is much weaker than that of rat neutral cholesterol esterase. These results indicate (1) that the difference in endocrine toxicological events between rats and monkeys is mainly due to inhibition of steroidogenesis by SMP-028 in rats, not in monkeys, and (2) that SMP-028 may not affect steroidogenesis in humans and therefore might cause no endocrine toxicological events in clinical studies. - Highlights: • SMP-028 inhibitsmore » neutral CEase more strongly than other steroidogenic enzymes in rats. • Inhibition of neutral CEase in rats by SMP-028 suppresses steroidogenesis in vivo. • SMP-028 does not inhibit neutral CEase in monkeys in vivo. • Steroidogenesis pathway in monkeys treated with SMP-028 was not suppressed. • SMP-028 may not inhibit LIPE in humans in vivo.« less
Authors:
 [1] ;  [1] ;  [2] ; ;  [1] ;  [3] ;  [1]
  1. Preclinical Research Laboratories, Dainippon Sumitomo Pharma Co., Ltd., 33-94, Enoki-cho, Suita, Osaka 564-0053 (Japan)
  2. Research Planning and Intelligence, Dainippon Sumitomo Pharma Co., Ltd., 33-94, Enoki-cho, Suita, Osaka 564-0053 (Japan)
  3. Innovative Drug Discovery Laboratories, Dainippon Sumitomo Pharma Co., Ltd., 33-94, Enoki-cho, Suita, Osaka 564-0053 (Japan)
Publication Date:
OSTI Identifier:
22439707
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 276; Journal Issue: 3; Other Information: Copyright (c) 2014 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ASTHMA; CHOLESTEROL; DOSES; DRUGS; FIBROBLASTS; GENES; HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY; IN VIVO; MONKEYS; NADP; OVARIES; PATHOLOGICAL CHANGES; RATS; RECEPTORS; SAFETY; TESTOSTERONE; TOXICITY