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Genotoxicity and carcinogenicity risk assessment of prucalopride, a selective 5-hydroxytryptamine 4 receptor agonist.
Regulatory Toxicology and Pharmacology ( IF 3.0 ) Pub Date : 2020-01-20 , DOI: 10.1016/j.yrtph.2020.104586
Hong Wang 1 , Kate Lane 2 , Zhen Lou 1 , Suezanne Parker 3 , Michael Placke 1
Affiliation  

Prucalopride, a high affinity, selective serotonin type 4 (5-HT4) receptor agonist, was associated with increased neoplasia incidence (in endocrine tissues and liver) in 2-year rodent bioassays, without evidence of a genotoxic mechanism of action. Proposed mechanisms of action involve prolactin and the constitutive androstane receptor (CAR). Epigenetic mechanisms and their relevance to humans are discussed. Data from in vitro and in vivo rodent studies demonstrated that prucalopride-related stimulation of prolactin secretion (via dopamine receptor D2 antagonism at high doses) is a rodent-specific, non-genotoxic mechanism for inducing hyperplasia and neoplasia in prolactin receptor-expressing endocrine tissues. Additional data demonstrated that CAR-mediated liver enzyme induction underlies the observed hepatocellular adenomas and thyroid follicular adenomas in rodents. A 12-month neonatal mouse carcinogenicity study confirmed the lack of a genotoxic mechanism of action. Furthermore, tumors were observed only at very high exposures (200 and 63 fold higher in mice and rats, respectively, than human exposure after a daily therapeutic dose of 2 mg). The studies indicate that non-genotoxic, rodent-specific, epigenetic mechanisms that are considered clinically irrelevant are responsible for the increased incidence of neoplasias associated with very high exposure to prucalopride in rodents, and that prucalopride does not pose a carcinogenic safety risk to humans.

中文翻译:

普鲁卡必利的遗传毒性和致癌性风险评估,一种选择性的5-羟基色胺4受体激动剂。

Prucalopride是一种高亲和力的选择性4型5-羟色胺选择性受体激动剂,在两年的啮齿类动物生物测定中与肿瘤形成(在内分泌组织和肝脏中)的发生率增加相关,而没有基因毒性作用机理的证据。提议的作用机制涉及催乳激素和组成型雄烷受体(CAR)。讨论了表观遗传机制及其与人类的关系。体外和体内啮齿动物研究的数据表明,普鲁氯必利相关的催乳素分泌刺激(通过高剂量的多巴胺受体D2拮抗作用)是一种啮齿类动物特异性的非基因毒性机制,可在表达催乳素受体的内分泌组织中诱导增生和赘生。 。其他数据表明,CAR介导的肝酶诱导是在啮齿动物中观察到的肝细胞腺瘤和甲状腺滤泡性腺瘤的基础。一项为期12个月的新生小鼠致癌性研究证实,缺乏基因毒性作用机制。此外,仅在非常高的暴露水平下观察到肿瘤(每日治疗剂量为2 mg后,小鼠和大鼠的暴露水平比人暴露水平高200和63倍)。研究表明,与临床无关的非遗传毒性,啮齿动物特异性,表观遗传机制是与啮齿类动物极高暴露于普考洛必德相关的肿瘤形成的增加的原因,并且普考洛必德不会对人类构成致癌的安全风险。一项为期12个月的新生小鼠致癌性研究证实,缺乏基因毒性作用机制。此外,仅在非常高的暴露水平下观察到肿瘤(每日治疗剂量为2 mg后,小鼠和大鼠的暴露水平比人暴露水平高200和63倍)。研究表明,与临床无关的非遗传毒性,啮齿动物特异性,表观遗传机制是与啮齿类动物极高暴露于普考洛必德相关的肿瘤形成的增加的原因,并且普考洛必德不会对人类构成致癌的安全风险。一项为期12个月的新生小鼠致癌性研究证实,缺乏基因毒性作用机制。此外,仅在非常高的暴露水平下观察到肿瘤(每日治疗剂量为2 mg后,小鼠和大鼠的暴露水平比人暴露水平高200和63倍)。研究表明,与临床无关的非遗传毒性,啮齿动物特异性,表观遗传机制是与啮齿类动物极高暴露于普考洛必德相关的肿瘤形成的增加的原因,并且普考洛必德不会对人类构成致癌的安全风险。
更新日期:2020-01-21
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