Human Cytochrome P450 1, 2, 3 Families as Pharmacogenes with Emphases on Their Antimalarial and Antituberculosis Drugs and Prevalent African Alleles

Abstract

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 CYP2A6*17, CYP2A6*23, CYP2A6*25, CYP2A6*28, CYP2B6*6, CYP2B6*18, CYP2C8*2, CYP2C9*5, CYP2C9*8, CYP2C9*9, CYP2C19*9, CYP2C19*13, CYP2C19*15, CYP2D6*2, CYP2D6*17, CYP2D6*29, 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.

The Mechanism of Vascular Endothelial Dysfunction Induced by Ferroptosis Mediated by NARFL Knockout

“…It can also interact with 15-lipoxygenase to metabolize arachidonic acid and convert hydroperoxicosatetraenoates (HpETEs) into hydroxy epoxy eicosatrienoates (HEETs) 29 . HEETs have been shown to play a protective role in vascular injury through various mechanisms, including anti-inflammation, anti-apoptosis, and inhibition of vascular endothelial cell aging 29, 30 . In summary, a decrease in the expression of CYP2J2 results in a reduction in HEET levels, thereby diminishing the protective effect on blood vessels.…”

CYP2C19 and CYP2J2 genotypes predict praziquantel plasma exposure among Ethiopian school-aged children

“…CYP2J2 metabolizes structurally diverse compounds that are also metabolized by CYP3A4 , but with differences in regioselectivity 35 , 38 . In addition to its role in endogenous metabolism, recent studies highlighted the importance of CYP2J2 for metabolizing various drugs, including anti-malarial and anti-tuberculosis that are widely used in Africa 39 , 40 . For the first time, our result indicates CYP2J2 genotype plays an important role in inter-individual variability in PZQ and its metabolites exposure.…”

Therapeutic efficacy of generic artemether–lumefantrine in the treatment of uncomplicated malaria in Ghana: assessing anti-malarial efficacy amidst pharmacogenetic variations

“…Plasma lumefantrine concentration for CYP3A5 *1/*1 was lower than other genotypes such as *1/*3, *1/*6, *1/*7 and *3/*6. There have been limited studies undertaken on CYP3A4 - CYP3A5 genotypes and their effects on AL, however, the role of CYP3A4 and CYP3A5 in artemether and DHA metabolism is highly elucidated [ 45 , 46 ]. One of the determinants of plasma artemether and LUM concentrations is the CYP3A pharmacogenetic status of an individual.…”