Division of Biomedical Science, School of Pharmacy, University of Nottingham Malaysia, Selangor, Malaysia.
School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia.
Hum Exp Toxicol. 2020 Jun;39(6):785-796. doi: 10.1177/0960327120905959. Epub 2020 Feb 13.
Cytochrome P450 4B1 (CYP4B1) plays crucial roles in biotransforming of xenobiotics. Its predominant extrahepatic expression has been associated with certain tissue-specific toxicities. However, the expressions of CYP4B1 in various cancers and hence their potential roles in cancer development were inclusive. In this work, existing knowledge on expression and regulation of CYP4B1 gene and protein, catalysis of CYP4B1, association of CYP4B1 with cancers, contradicting findings about human CYP4B1 activities as well as the employing CYP4B1 in suicide gene approach for cancer treatment were reviewed. To date, it appears that there is a wide spectrum of tissue distribution of CYP4B1 with lungs as the predominant sites. Several nuclear receptors are possibly responsible for regulating its gene expression. The involvement of CYP4B1 in cancer was considered via activation of procarcinogens and neovascularization. However, human CYP4B1 was found to be inactive due to a substitution of proline with serine at position 427. Suicide gene approach combining reengineered CYP4B1 and prodrug 4-ipomeanol (4-IPO) has shown a promising potential for targeted cancer therapy. Further studies should focus on the verification of human CYP4B1 catalytic activities. More compounds with similar structure as 4-IPO should be tested to identify more alternative agents for the suicide gene approach in cancer treatment.
细胞色素 P450 4B1（CYP4B1）在生物转化外来物质方面发挥着关键作用。其在肝外的主要表达与某些组织特异性毒性有关。然而，CYP4B1 在各种癌症中的表达及其在癌症发展中的潜在作用尚不清楚。在这项工作中，我们回顾了 CYP4B1 基因和蛋白质的表达和调节、CYP4B1 的催化作用、CYP4B1 与癌症的关联、关于人 CYP4B1 活性的矛盾发现，以及将 CYP4B1 应用于自杀基因方法治疗癌症等方面的现有知识。迄今为止，CYP4B1 的组织分布似乎很广泛，肺部是主要部位。几种核受体可能负责调节其基因表达。CYP4B1 可能通过激活前致癌物和新生血管化参与癌症的发生。然而，由于第 427 位脯氨酸被丝氨酸取代，人 CYP4B1 被认为是无活性的。结合改良后的 CYP4B1 和前药 4-异丙基吗啉（4-IPO）的自杀基因方法已显示出靶向癌症治疗的巨大潜力。进一步的研究应集中在验证人 CYP4B1 的催化活性上。应该测试更多具有类似 4-IPO 结构的化合物，以确定自杀基因方法在癌症治疗中的更多替代药物。
