The <i>CYP3A4</i> intron 6 C>T polymorphism (<i>CYP3A4*22</i>) is associated with reduced CYP3A4 protein level and function in human liver microsomes

Abstract

Effects of the CYP3A4 intron 6 C>T (CYP3A4*22) polymorphism, which has recently been reported to have a critical role in vivo, were investigated by measuring CYP3A4 protein expression levels and CYP3A4-dependent drug oxidation activities in individual human liver microsomes in vitro. Prior to protein analysis, analysis of DNA samples indicated that 36 Caucasian subjects were genotyped as CYP3A4*1/*1 and five subjects were CYP3A4*1/*22, with a CYP3A4*22 allelic frequency of 6.1%. No CYP3A4*22 alleles were found in the Japanese samples (106 alleles). Individual differences in CYP2D6-dependent dextromethorphan O-demethylation activities in liver microsomes from Caucasians were not affected by either the CYP3A4*1/*22 or CYP3A5*1/*3 genotype. Liver microsomes genotyped as CYP3A4*1/*22 (n=4) showed significantly lower CYP3A-dependent dextromethorphan N-demethylation, midazolam 1′-hydroxylation, and testosterone 6β-hydroxylation activities, as well as lower expression levels of CYP3A protein (28% of control), compared with those of the CYP3A4*1/*1 group (n=19). The other polymorphism, CYP3A5*1/*3, did not show these differences (n=4). The CYP3A4*22 polymorphism was associated with reduced CYP3A4 protein expression levels and resulted in decreased CYP3A4-dependent activities in human livers. The present results suggest an important role of low expression of CYP3A4 protein associated with the CYP3A4*22 allele in the individual differences in drug clearance.

Influence of Cytochrome P450 (CYP) <i>3A4*1G</i> Polymorphism on the Pharmacokinetics of Tacrolimus, Probability of Acute Cellular Rejection, and mRNA Expression Level of CYP3A5 Rather than CYP3A4 in Living-Donor Liver Transplant Patients

“…7,9,21,22) Although some SNPs in the CYP3A4 gene such as CYP3A4*1B and CYP3A4*22 have been reported to affect the pharmacokinetics of tacrolimus, 17,23) the frequencies of CYP3A4*1B and CYP3A4*22 have not been observed in Chinese and Japanese patients. 19,[24][25][26] In the present study, CYP3A4*1G genotype showed a significant association with the C/D ratio of tacrolimus in living-donor liver transplant patients comparable with data reported in kidney transplantation. 9) We showed CYP3A4*1G genotype had no correlation with the mRNA expression level of CYP3A4 both in graft liver and native intestine.…”

Frequency of CYP450 enzyme gene polymorphisms in the Greek population: review of the literature, original findings and clinical significance

“…Recently, a novel functional SNP located in intron 6 of CYP3A4 (CYP3A4*22, rs35599367) was identified and fully correlated with the observed allelic mRNA pattern, Brought to you by | Kungliga Tekniska Högskolan Authenticated Download Date | 7/4/15 5:33 AM CYP3A4 total mRNA level and activity in human livers [84,85]. CYP3A4*22 allele has emerged as a novel important biomarker for identifying reduced metabolism of CYP3A4 drugs and has been associated with reduced dose requirements for optimal pharmacotherapy with the drugs simvastatin, tacrolimus and cyclosporine [30].…”

Association of Plasma Concentration of 4β-Hydroxycholesterol with CYP3A5 Polymorphism and Plasma Concentration of Indoxyl Sulfate in Stable Kidney Transplant Recipients

“…This result suggests that CYP3A5 is involved primarily in the formation of 4b-hydroxycholesterol in Japanese stable kidney transplant recipients. Other polymorphisms of CYP3A5, such as CYP3A5*2, CYP3A5*4, and CYP3A5*5, and those of CYP3A4, such as CYP3A4*1B, CYP3A4*4, CYP3A4*16, CYP3A4*18, and CYP3A4*22 were not genotyped in this study because of the low frequencies of these genotypes in the Japanese population (Hiratsuka et al, 2002;Lamba et al, 2002;Yamamoto et al, 2003;Goto et al, 2004;Nakajima et al, 2005;Okubo et al, 2013). Further studies, probably across populations, would help to understand the effects of these polymorphisms on plasma concentrations of 4b-hydroxycholesterol.…”