title: Translational research into species differences of endocrine toxicity via steroidogenesis inhibition by SMP-028--for human safety in clinical study.
abstract: 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.
authors.affiliation: Preclinical Research Laboratories, Dainippon Sumitomo Pharma Co., Ltd., 33-94, Enoki-cho, Suita, Osaka 564-0053, Japan. Electronic address: yohei-nishizato@ds-pharma.co.jp.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Nishizato
authors.affiliation: Preclinical Research Laboratories, Dainippon Sumitomo Pharma Co., Ltd., 33-94, Enoki-cho, Suita, Osaka 564-0053, Japan.
authors.forename: Satoki
authors.initials: S
authors.lastname: Imai
authors.affiliation: Research Planning & Intelligence, Dainippon Sumitomo Pharma Co., Ltd., 33-94, Enoki-cho, Suita, Osaka 564-0053, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Okahashi
authors.affiliation: Preclinical Research Laboratories, Dainippon Sumitomo Pharma Co., Ltd., 33-94, Enoki-cho, Suita, Osaka 564-0053, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Yabunaka
authors.affiliation: Preclinical Research Laboratories, Dainippon Sumitomo Pharma Co., Ltd., 33-94, Enoki-cho, Suita, Osaka 564-0053, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kunimatsu
authors.affiliation: Innovative Drug Discovery Laboratories, Dainippon Sumitomo Pharma Co., Ltd., 33-94, Enoki-cho, Suita, Osaka 564-0053, Japan.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Kikuchi
authors.affiliation: Preclinical Research Laboratories, Dainippon Sumitomo Pharma Co., Ltd., 33-94, Enoki-cho, Suita, Osaka 564-0053, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Yabuki
mesh_terms: D000818:Animals; D018927:Anti-Asthmatic Agents / Q000633:toxicity*; D019556:COS Cells; D002522:Chlorocebus aethiops; D004702:Endocrine Glands / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D000882:Haplorhini; D006801:Humans; D008297:Male; D008782:Methylurea Compounds / Q000633:toxicity*; D051381:Rats; D013045:Species Specificity; D013256:Steroids / Q000096:biosynthesis*; D002787:Sterol Esterase / Q000037:antagonists & inhibitors; D013844:Thiazoles / Q000633:toxicity*; D057170:Translational Research, Biomedical
chemical_list: D018927:Anti-Asthmatic Agents; D008782:Methylurea Compounds; C000588743:N-(2-(2-((3-fluorophenyl)imino)-4-(4-morpholin-4-ylphenyl)-1,3-thiazol-3(2H)-yl)ethyl)-N'-methylurea; D013256:Steroids; D013844:Thiazoles; D002787:Sterol Esterase
keywords: Cholesterol esterase; Endocrine organ; Endocrine toxicity; Human; Species difference; Translational research