Research Unit in Bioinformatics (RUBi), Department of Biochemistry and Microbiology, Rhodes University, Makhanda 6139, South Africa.
Translational Medicine, Novartis Institutes for BioMedical Research, 220 Massachusetts Ave, Cambridge, MA 02139, USA.
Int J Mol Sci. 2023 Feb 8;24(4):3383. doi: 10.3390/ijms24043383.
Precision medicine gives individuals tailored medical treatment, with the genotype determining the therapeutic strategy, the appropriate dosage, and the likelihood of benefit or toxicity. Cytochrome P450 (CYP) enzyme families 1, 2, and 3 play a pivotal role in eliminating most drugs. Factors that affect CYP function and expression have a major impact on treatment outcomes. Therefore, polymorphisms of these enzymes result in alleles with diverse enzymatic activity and drug metabolism phenotypes. Africa has the highest CYP genetic diversity and also the highest burden of malaria and tuberculosis, and this review presents current general information on CYP enzymes together with variation data concerning antimalarial and antituberculosis drugs, while focusing on the first three CYP families. Afrocentric alleles such as CYP2A617, CYP2A623, CYP2A625, CYP2A628, CYP2B66, CYP2B618, CYP2C82, CYP2C95, CYP2C98, CYP2C99, CYP2C199, CYP2C1913, CYP2C1915, CYP2D62, CYP2D617, CYP2D629, and CYP3A4*15 are implicated in diverse metabolic phenotypes of different antimalarials such as artesunate, mefloquine, quinine, primaquine, and chloroquine. Moreover, CYP3A4, CYP1A1, CYP2C8, CYP2C18, CYP2C19, CYP2J2, and CYP1B1 are implicated in the metabolism of some second-line antituberculosis drugs such as bedaquiline and linezolid. Drug-drug interactions, induction/inhibition, and enzyme polymorphisms that influence the metabolism of antituberculosis, antimalarial, and other drugs, are explored. Moreover, a mapping of Afrocentric missense mutations to CYP structures and a documentation of their known effects provided structural insights, as understanding the mechanism of action of these enzymes and how the different alleles influence enzyme function is invaluable to the advancement of precision medicine.
精准医学为个体提供量身定制的医疗，其治疗策略取决于基因型、合适的剂量以及获益或毒性的可能性。细胞色素 P450（CYP）酶家族 1、2 和 3 在消除大多数药物方面发挥着关键作用。影响 CYP 功能和表达的因素对治疗结果有重大影响。因此，这些酶的多态性导致具有不同酶活性和药物代谢表型的等位基因。非洲拥有最高的 CYP 遗传多样性，也是疟疾和结核病负担最高的地区，本综述介绍了 CYP 酶的当前一般信息以及抗疟药和抗结核药的变异数据，重点介绍了前三类 CYP 酶家族。非裔等位基因，如 CYP2A617、CYP2A623、CYP2A625、CYP2A628、CYP2B66、CYP2B618、CYP2C82、CYP2C95、CYP2C98、CYP2C99、CYP2C199、CYP2C1913、CYP2C1915、CYP2D62、CYP2D617、CYP2D629 和 CYP3A4*15，与青蒿琥酯、甲氟喹、奎宁、伯氨喹和氯喹等不同抗疟药的多种代谢表型有关。此外，CYP3A4、CYP1A1、CYP2C8、CYP2C18、CYP2C19、CYP2J2 和 CYP1B1 与乙胺嘧啶和利奈唑胺等一些二线抗结核药物的代谢有关。本文探讨了影响抗结核、抗疟和其他药物代谢的药物-药物相互作用、诱导/抑制以及酶多态性。此外，将非裔等位基因错义突变映射到 CYP 结构，并记录其已知影响，提供了结构见解，因为了解这些酶的作用机制以及不同等位基因如何影响酶功能对于推进精准医学至关重要。
