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  • Introduction Cytochrome P CYP A is the most important

    2019-11-28

    Introduction Cytochrome P450 (CYP)3A is the most important enzyme involved in the metabolism of 30–40% of currently prescribed drugs [1]. The 5-Hydroxy-CTP level and activity of CYP3A show large intra- and inter-individual variability, which contributes to unpredictable drug response and toxicity. A multitude of environmental, physiologic, and genetic factors have been reported to influence the variability of CYP3A expression and activity [2]. CYP3A5 exhibits genetic polymorphisms, and the most common loss-of-function variant is designated CYP3A5*3 (rs776746, 6986 A > G) [3]. People homozygous for the CYP3A5*3 allele (poor metabolizers) show lower clearance of CYP3A5 substrates such as tacrolimus [4], cilostazol [5], and verapamil [6] than people heterozygous (intermediate metabolizers) or homozygous for the CYP3A5*1 allele (extensive metabolizers). However, some extensive metabolizers transiently exhibit similar level of CYP3A activity as in poor metabolizers, although they should have higher metabolic capacity genetically. This phenomenon, in which a genotypic extensive metabolizer is converted transiently to phenotypic poor metabolizer, is called phenoconversion [7]. Phenoconversion has been reported for several drug metabolizing enzymes. Phenoconversion of CYP2D6 is most commonly reported in patients with various diseases such as human immunodeficiency virus infection [8,9], chronic hepatitis C virus infection [10], and depression [11]. Especially, the largest scale study reported by Preskorn et al. [11] showed phenoconversion of CYP2D6 in 24% of patients with depression. Phenoconversion was also reported for CYP2C19, and 25%–37% of genotypic extensive metabolizers exhibited poor metabolizer phenotype [[12], [13], [14]]. On the other hand, to the best of our knowledge, whether phenoconversion of CYP3A occurs in patients remains unknown. Renal failure is known to decrease CYP3A activity in humans [15]. Some uremic toxins, parathyroid hormone (PTH), and inflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) have been reported to induce downregulation of CYP3A in renal failure, in both in vitro [[16], [17], [18], [19], [20], [21], [22]] and in vivo experiments [19]. Recently, we reported that accumulation of indoxyl sulfate, a uremic toxin, was involved in the decrease in CYP3A activity in patients with chronic renal failure [23], although the clinical effects of PTH, IL-6 and TNF-α in humans are unknown. These substances have the potential to be involved in phenoconversion of CYP3A in patients with chronic renal failure. Based on this hypothesis, we determined CYP3A5 polymorphism in stable kidney transplant recipients, and measured plasma concentrations of indoxyl sulfate, PTH, IL-6 and TNF-α and evaluated their relations with CYP3A phenoconversion evaluated by plasma concentration of 4β-hydroxycholesterol, a biomarker of CYP3A activity. In this cross-sectional study, we defined CYP3A phenoconversion as a genotypic extensive/intermediate metabolizer (with CYP3A5*1 allele) exhibiting CYP3A activity below the cutoff value that discriminates between extensive/intermediate (with CYP3A5*1 allele) and poor metabolizers (without CYP3A5*1 allele).
    Materials and methods
    Results Table 1 shows the clinical data of the 63 recipients. They comprised 23 recipients with CYP3A5*1 allele (CYP3A5*1/*1 or *1/*3) and 40 recipients without CYP3A5*1 allele (CYP3A5*3/*3). Plasma concentration (mean ± SD) of 4β-hydroxycholesterol was 36.4 ± 11.7 ng/mL; indoxyl sulfate was 12.0 ± 11.8 μM, and intact-PTH, IL-6 and TNF-α were 151.9 ± 141.8, 1.9 ± 1.7 and 2.1 ± 2.1 pg/mL, respectively. Large inter-individual variations were observed in all the parameters measured. When recipients were divided by CYP3A5 polymorphism into two groups, significantly higher plasma 4β-hydroxycholesterol concentration was observed in recipients with CYP3A5*1 allele (n = 23) compared to those without CYP3A5*1 allele (n = 40) (40.2 ± 13.1 vs. 34.2 ± 10.3 ng/mL, p <  0.05). CART analysis identified plasma 4β-hydroxycholesterol concentration of 40.0 ng/mL as the cutoff value for discriminating between recipients with CYP3A5*1 allele and those without this allele. According to our definition, recipients with CYP3A5*1 allele (CYP3A5*1/*1 or CYP3A5*1/*3) who had plasma 4β-hydroxycholesterol concentrations below 40 ng/mL were considered to show phenoconversion of CYP3A.