The effect of genetic polymorphisms in CYP2C9 on sulphamethoxazole N-hydroxylation

Gill, Helen; Tjia, John; Kitteringham, Neil R.; Pirmohamed, Munir; Back, David; Park, B.

doi:10.1097/00008571-199902000-00007

Cited by 43 publications

(26 citation statements)

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“…For example, the clearance of S-warfarin is decreased by 66% in CYP2C9*3 heterozygotes, 23 but this genotype has no effect on the biotransformation of other CYP2C9 drug substrates such as diclofenac [29][30][31][32] and sulfamethoxazole. 33 In the present study, the formation rates of the 4-ene, 4-OH-, and 5-OH-VPA metabolite (at 1 mM substrate concentration) in human liver microsomes with the CYP2C9*1/*2, CYP2C9*1/*3, CYP2C9*2/*2, or CYP2C9*2/*3 genotype were not significantly different from those in the CYP2C9*1/*1 group. An explanation for this finding is the small number of samples analyzed, particularly in the CYP2C9*2/*2 and CYP2C9*2/*3 groups.…”

Section: Pc Ho Et Alcontrasting

confidence: 42%

Influence of CYP2C9 genotypes on the formation of a hepatotoxic metabolite of valproic acid in human liver microsomes

Abbott

Zanger

et al. 2003

Pharmacogenomics J

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The present study investigated the effect of cytochrome P450 2C9 (CYP2C9) genetic polymorphism on the biotransformation of valproic acid (VPA) to its hepatotoxic metabolite, 4-ene-VPA, and compared that to the formation of the inactive 4-OH-VPA and 5-OH-VPA. cDNA-expressed CYP2C9*2 and CYP2C9*3 variants were less efficient than the CYP2C9*1 wild type in catalyzing the formation of these metabolites, as assessed by the ratio of Vmax and apparent Km (in vitro intrinsic clearance). The reduced efficiency by CYP2C9*2 was due to a reduced Vmax, whereas, in the case of CYP2C9*3, it was the result of increased apparent Km. The formation rates of 4-ene-VPA, 4-OH-VPA, and 5-OH-VPA in human liver microsomes were reduced by 29, 28, and 31%, respectively, in samples with one mutated CYP2C9 allele, and by 61, 73, and 58%, respectively, in samples with two mutated CYP2C9 alleles. Overall, the homozygote and heterozygote CYP2C9*2 and CYP2C9*3 genotypes may compromise hepatic VPA biotransformation.

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Section: Pc Ho Et Alcontrasting

confidence: 42%

Influence of CYP2C9 genotypes on the formation of a hepatotoxic metabolite of valproic acid in human liver microsomes

Abbott

Zanger

et al. 2003

Pharmacogenomics J

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“…It is possible that variability in CYP3A4 activity determines the extent of primary TMP bioactivation in vivo, and further studies are underway to assess the extent of primary TMP metabolism variability in vivo. Hence, factors modulating activity of these contributing enzymes may affect the risk of adverse drug reactions (Gill et al, 1999).…”

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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“…[38][39][40] Most of the other drug classes associated with a high incidence of immunological reactions are chemically inert; however, through normal processes of drug metabolism, protein-reactive intermediates may be generated. [41][42][43] Using advanced technologies, such as mass spectrometry, it is possible to define the chemistry of drug-protein conjugation in patients and the nature of the drug-derived epitopes, which can function as an antigen to stimulate T cells. [44][45][46][47][48] There is another mechanism underlying drug-specific T-cell activation.…”

Section: Drug Antigenicitymentioning

confidence: 99%

Update on Advances in Research on Idiosyncratic Drug-Induced Liver Injury

Kim

Naisbitt

2016

Allergy Asthma Immunol Res

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This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Drug-induced liver injury (DILI) is a major concern for public health, as well as for drug development in the pharmaceutical industry, since it can cause liver failure and lead to drug withdrawal from the market and black box warnings. Thus, it is important to identify biomarkers for early prediction to increase our understanding of mechanisms underlying DILI that will ultimately aid in the exploration of novel therapeutic strategies to prevent or manage DILI. DILI can be subdivided into 'intrinsic' and 'idiosyncratic' categories, although the validity of this classification remains controversial. Idiosyncratic DILI occurs in a minority of susceptible individuals with a prolonged latency, while intrinsic DILI results from drug-induced direct hepatotoxicity over the course of a few days. The rare occurrence of idiosyncratic DILI requires multicenter collaborative investigations and phenotype standardization. Recent progress in research on idiosyncratic DILI is based on key developments in 3 areas: (1) newly developed highthroughput genotyping across the whole genome allowing for the identification of genetic susceptibility markers, (2) new mechanistic concepts on the pathogenesis of DILI revealing a key role of drug-responsive T lymphocytes in the immunological response, and (3) broad multidisciplinary approaches using different platform "-omics" technologies that have identified novel biomarkers for the prediction of DILI. An association of a specific human leukocyte antigen (HLA) allele with DILI has been reported for several drugs. HLA-restricted T-cell immune responses have also been investigated using lymphocytes and T-cell clones isolated from patients. A microRNA, miR-122, has been discovered as a promising biomarker for the early prediction of DILI. In this review, we summarize recent advances in research on idiosyncratic DILI with an understanding of the key role of adaptive immune systems.

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The effect of genetic polymorphisms in CYP2C9 on sulphamethoxazole N-hydroxylation

Cited by 43 publications

References 0 publications

Influence of CYP2C9 genotypes on the formation of a hepatotoxic metabolite of valproic acid in human liver microsomes

Influence of CYP2C9 genotypes on the formation of a hepatotoxic metabolite of valproic acid in human liver microsomes

In Vitro Hepatic Oxidative Biotransformation of Trimethoprim

Update on Advances in Research on Idiosyncratic Drug-Induced Liver Injury

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