Functional Gene Variants of CYP3A4

Werk, Anneke Nina; Cascorbi, Ingolf

doi:10.1038/clpt.2014.129

Cited by 208 publications

(150 citation statements)

References 73 publications

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“…Genotypic variation in CYP2C9 and CYP3A4 alleles can lead to alterations in the activity of these enzymes (Kirchheiner and Brockmoller, 2005;Werk and Cascorbi, 2014), which has the potential to alter the balance between bioactivation and detoxification, and thus alter the relative abundance of reactive and stable TMP metabolites. Further studies assessing in vivo TMP bioactivation are needed to better understand the extent and variability of TMP bioactivation in humans.…”

Section: Discussionmentioning

confidence: 99%

In Vitro Hepatic Oxidative Biotransformation of Trimethoprim

et al. 2015

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Trimethoprim (TMP) has been widely used since the 1960s, both alone and in combination with sulfamethoxazole. Unfortunately, information regarding the role that cytochrome P450 enzymes (P450s) play in the formation of TMP primary metabolites is scarce. Hence, we undertook in vitro studies to identify and more fully characterize the P450s that catalyze formation of six TMP primary metabolites: TMP 1-N-oxide (1-NO-TMP) and 3-N-oxide (3-NO-TMP), 39-and 49-desmethyl-TMP, a benzylic alcohol (Ca-OH-TMP), and an N-acetyl cysteine (NAC) adduct of TMP (Ca-NAC-TMP). Formation kinetics for each TMP metabolite in human liver microsomes (HLMs) were consistent with single-enzyme Michaelis-Menten kinetics, and K m values were markedly above ( ‡10-fold) the therapeutic concentrations of TMP (50 mM). The combined results from correlation studies between rates of metabolite formation and marker P450 activities in a panel of HLMs along with inhibition studies utilizing selective P450 inhibitors incubated with pooled HLMs suggested that 1-NO-TMP, Ca-NAC-TMP, and Ca-OH-TMP were predominantly formed by CYP3A4. In contrast, 3-NO-TMP was formed predominantly by CYP1A2 in HLMs and inhibited by a-naphthoflavone. 49-Des met hy l-T MP, which is believed to be a reactive TMP metabolite precursor, was formed by several P450s, including CYP3A4, correlated with multiple P450 activities, but was inhibited primarily by ketoconazole (up to 50%), suggesting that CYP3A4 makes a major contribution to TMP 49-demethylation. TMP 39-demethylation was catalyzed by multiple P450s, including CYP2C9, correlated with CYP2C9 activity, and was inhibited by sulfaphenazole (up to 40%). Overall, CYP2C9 and CYP3A4 appear to be the most significant contributors to TMP primary metabolism.

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Section: Discussionmentioning

confidence: 99%

In Vitro Hepatic Oxidative Biotransformation of Trimethoprim

et al. 2015

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“…[40] This variant is a c.802C>T transition and results in a premature stop codon at position 268 in exon 9 (R268*). [40] The resulting truncated CYP3A4 protein is nonfunctional.…”

Section: Cyp3a4mentioning

confidence: 99%

“…[40] This variant is a c.802C>T transition and results in a premature stop codon at position 268 in exon 9 (R268*). [40] The resulting truncated CYP3A4 protein is nonfunctional. Werk et al [41] first identified this mutation when they observed an unusually low Tac dose requirement in a kidney transplant recipient.…”

Section: Cyp3a4mentioning

confidence: 99%

Pharmacogenetic aspects of the use of tacrolimus in renal transplantation: recent developments and ethnic considerations

Tang

Andrews

Gelder

et al. 2016

Expert Opinion on Drug Metabolism & Toxicology

114

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Introduction: Tacrolimus (Tac) is effective in preventing acute rejection but has considerable toxicity and inter-individual variability in pharmacokinetics and pharmacodynamics. Part of this is explained by polymorphisms in genes encoding Tac-metabolizing enzymes and transporters. A better understanding of Tac pharmacokinetics and pharmacodynamics may help to minimize different outcomes amongst transplant recipients by personalizing immunosuppression. Areas covered: The pharmacogenetic contribution of Tac metabolism will be examined, with a focus on recent discoveries, new developments and ethnic considerations. Expert opinion: The strongest and most consistent association in pharmacogenetics is between the CYP3A5 genotype and Tac dose requirement, with CYP3A5 expressers having a~40-50% higher dose requirement compared to non-expressers. Two recent randomized-controlled clinical trials using CYP3A5 genotype, however, did not show a decrease in acute rejections nor reduced toxicity. CYP3A4*22, CYP3A4*26, and POR*28 are also associated with Tac dose requirements and may be included to provide the expected improvement of Tac therapy. Studies focusing on the intracellular drug concentrations and on calcineurin inhibitor-induced nephrotoxicity also seem promising. For all studies, however, the ethnic prevalence of genotypes should be taken into account, as this may significantly impact the effect of pre-emptive genotyping.ARTICLE HISTORY

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“…8 Functional variants in the CYP3A4 gene that may have functional effect have been characterized, but they are rare in Caucasian population. 17 One of the most common functional variants, CYP3A4*22 allele that leads to decreased enzyme activity has a frequency of 5-7% in Caucasian populations. 18 Therefor we would need a much larger sample to investigate the potential role of this polymorphism in 21OHD genotype -phenotype inconsistency.…”

Section: Resultsmentioning

confidence: 99%

Clinical Role of CYP2C19 Polymorphisms in Patients with Congenital Adrenal Hyperplasia Due to 21-hydroxylase Deficiency

Grošelj¹,

Tanšek²,

Podkrajšek³

et al. 2016

ACSi

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Extraadrenal enzymes such as CYP2C19 may participate in residual 21-hydroxylation of progesterone leading to milder phenotypes of congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD). Among 94 21OHD patients from the Slovene national registry 28 were homozygous or compound heterozygous for severe CYP21A2 mutations. We have reviewed their clinical phenotype and obtained information on maintenance doses of hydrocortisone and fludrocortisone. All patients were genotyped for CYP2C19*2 and CYP2C19*17 alleles. Among eleven patients with CYP2C19*1/*17 genotype, all had salt-wasting 21OHD. Out of 17 patients with CYP2C19 genotypes leading to normal or decreased CYP2C19 activity, 15 had salt-wasting, one had simple virilizing and one had non-classical 21OHD. CYP2C19*1/*17 genotype was associated with lower maintenance dose of fludrocortisone (p = 0.04), but not of hydrocortisone (p > 0.05). Increased CYP2C19 activity could slightly ameliorate mineralocorticoid deficiency in 21OHD.

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Functional Gene Variants of CYP3A4

Cited by 208 publications

References 73 publications

In Vitro Hepatic Oxidative Biotransformation of Trimethoprim

In Vitro Hepatic Oxidative Biotransformation of Trimethoprim

Pharmacogenetic aspects of the use of tacrolimus in renal transplantation: recent developments and ethnic considerations

Clinical Role of CYP2C19 Polymorphisms in Patients with Congenital Adrenal Hyperplasia Due to 21-hydroxylase Deficiency

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