Snyder Ronald D
Mechanistic and Predictive Toxicology, Dept of Genetic Toxicology, Schering-Plough Research Institute, Summit, New Jersey, USA.
Environ Mol Mutagen. 2009 Jul;50(6):435-50. doi: 10.1002/em.20485.
Information from the 1999 through 2008 Physicians' Desk Reference (PDR) was used to evaluate the genotoxicity of marketed drugs. Where available, data regarding the rodent carcinogenicity results were included (PDR and Gold potency database). In addition, computational predictivity of genotoxicity (DEREK, MC4PC) is included and expanded upon from two previous reviews. The present paper contains genotoxicity data on 545 marketed drugs. Excluded from analysis were most cytotoxic anti-cancer and antiviral drugs, nucleosides (all with known mechanistic genotoxicity), steroids with class-specific genotoxicity and biologicals or peptide-based drugs. Per assay type, the percentage of positive drugs was: Bacterial mutagenesis assay: 38/525 (7.1%), in vitro chromosome aberrations: 88/380 (26.1%); mouse lymphoma assays (MLA): 32/163 (19.1%), in vivo cytogenetics: 49/438 (11.1%). The relationship among positive genetic toxicity findings, rodent carcinogenicity, and in silico prediction is discussed. Finally, supporting evidence is presented for the idea that the presence of an N-dialkyl group or piperidine aryl ketone may somehow be associated with genotoxicity, perhaps through DNA intercalation and consequent DNA topoisomerase II inhibition.
利用1999年至2008年《医师案头参考》（PDR）中的信息评估市售药物的遗传毒性。如有可用信息，还纳入了啮齿动物致癌性结果的数据（PDR和黄金效力数据库）。此外，还纳入了遗传毒性的计算预测性（DEREK、MC4PC），并在前两篇综述的基础上进行了扩展。本文包含545种市售药物的遗传毒性数据。分析中排除了大多数细胞毒性抗癌和抗病毒药物、核苷（均具有已知的遗传毒性机制）、具有类别特异性遗传毒性的类固醇以及生物制品或肽类药物。每种检测类型的阳性药物百分比为：细菌诱变试验：38/525（7.1%），体外染色体畸变：88/380（26.1%）；小鼠淋巴瘤试验（MLA）：32/163（19.1%），体内细胞遗传学：49/438（11.1%）。讨论了阳性遗传毒性结果、啮齿动物致癌性和计算机预测之间的关系。最后，提出了支持性证据，证明N-二烷基或哌啶芳基酮的存在可能以某种方式与遗传毒性相关，可能是通过DNA嵌入以及随后的DNA拓扑异构酶II抑制作用。
