Genetic Variability in CYP3A5 and its Possible Consequences

Abstract

The cytochrome P450 3A (CYP3A) subfamily members are the most abundant and important drug-metabolizing enzymes in humans, and wide interindividual variability in CYP3A expression and function is present. CYP3A4 alone cannot fully explain the observed constitutive variability because its genetic variants are relatively uncommon and have limited functional significance, whereas CYP3A5 expression in humans is highly variable and may be contributory. However, it is difficult to delineate the relative contribution of CYP3A4 and CYP3A5, and to differentiate their effects on drug metabolism as their protein structure, function and substrates are so similar. By contrast, molecular biology methods provide the ability to identify CYP3A4 and CYP3A5 genotypes with certainty. This review collates currently available data on CYP3A5 polymorphisms, provides information on the population frequency of each genetic variant in major ethnic groups, and describes in vitro and in vivo studies that have attempted to identify genotype-phenotype associations.

Association of the CYP3A5 polymorphism (6986G>A) with blood pressure and hypertension

“…Given the large interethnic differences in allele frequencies, 41 a subgroup analysis based on ethnicity was performed. Except for hypertension risks in blacks, heterogeneity was not significant within each ethnic group.…”

Genetic polymorphisms of CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5 in Vietnamese-Koreans

“…[3] Finally, the frequency of CYP3A5*3 which is decreased activity allele also showed ethnic differences; Vietnamese-Koreans (78.4%), AfricanAmericans (32%), Caucasians (90-93%), Hispanics (65%), and South Asians (60%). [36,37] There are some limitations of the present study. First, only few Vietnamese-Korean subjects were genotyped for this study because it was hard to enroll that population.…”

Efeitos de hipolipemiantes sobre a expressão de CYP3A4 e CYP3A5 in vitro e in vivo

“…As CYP3A4 e CYP3A5 são codificadas pelos genes CYP3A4 e CYP3A5, que pertencem ao agrupamento CYP3A43-CYP3A4-CYP3AP2-CYP3A7-CYP3A5P1-CYP3A5, localizado no cromossomo 7 (7q21-q22.1). Nesse agrupamento, também estão localizados os genes que codificam os outros membros da subfamília CYP3A: CYP3A7 e CYP3A43 (XIE et al, 2004).…”

“…A CYP3A4 é o membro da subfamília CYP3A mais expresso em todas as populações estudadas (XIE et al, 2004). 48 SNPs no gene CYP3A4 foram descritos.…”

“…SNPs localizados nas regiões não traduzidas (untranslated region -UTR) das extremidades 5' e 3' do gene CYP3A5 também foram descritos (XIE et al, 2004 . A atorvastatina e a lovastatina são ligantes de PXR e CAR (LEHMAN et al, 1998;WAGNER et al, 2005;KOBAYASHI et al, 2005 TAKADA; SUZUKI et al, 2007;RODRIGUES et al, 2009a).…”