Paracetamol (acetaminophen) is a worldwide used analgesic and antipyretic drug. It is metabolised via several metabolic pathways, including glucuronidation, sulfation, oxidation, hydroxylation, and deacetylation: Hepatic and other organ damage may occur, especially in overdose, because of the accumulation of a toxic metabolite. Intersubject and ethnic differences have been reported in paracetamol metabolism activation, suggesting possible differences in susceptibility to toxicity and in pain alleviation, linked to different pharmacogenetic profiles. This article aims at reviewing, in the literature, the links between paracetamol metabolism and enzyme genotypes in the context of toxic side effects and efficacy of paracetamol in therapeutics.
KeywordsCYP2C9, CYP4F2, Chinese, mechanical heart valve replacement, VKORC1, warfarin
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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Genetic polymorphisms of VKORC1 and CYP2C9 are known to influence warfarin dosage.• Recent studies among Caucasians showed that polymorphisms of CYP4F2 also play a role in warfarin pharmacogenetics.• The contribution of CYP4F2 variants to the variability inwarfarin dose requirement in Chinese subjects remains to be investigated.
WHAT THIS STUDY ADDS• This research was to study the effect of CYP4F2 variants on warfarin requirements in the Han Chinese population.• This study developed a multiple regression model including CYP2C9, VKORC1 3673G>A, CYP4F2 genotypes and age, weight, combination use of amiodarone which could explain 56.1% of the individual variability in warfarin dose CYP4F2 could explain 4% of the variance in warfarin dose.• We found that one novel genotypic polymorphism 5417G>T for Asp36Tyr, which was identified as an important marker of warfarin resistance, was absent in the Han Chinese population in our study.
AIMSThe objective of this study was to assess the effect of the CYP4F2 on the daily stable warfarin dose requirement in Han Chinese patients with mechanical heart valve replacement (MHVR).
METHODS
From March 2007 to November 2008, 222Han Chinese MHVR patients were recruited in our study. VKORC1 3673G>A, 5417G>T, CYP2C9 *3 and CYP4F2 rs2108622 were genotyped by using the polymerase chain reaction restriction fragment length polymorphism method (PCR-RFLP). Polymorphisms of VKORC1 9041G>A were detected by direct sequencing. Multiple linear regression analysis was used to investigate the contribution of CYP4F2.
RESULTSThe CYP4F2 rs2108622 CT/TT group took a significantly higher stable warfarin dose (3.2 mg day
CONCLUSIONCYP4F2 is a minor significant factor of individual variability in the stable warfarin dose in Han Chinese patients with MHVR. The effect of CYP2C9 and VKORC1 genotypes on variability in the stable warfarin dose had also been confirmed.
A systematic review and a meta-analysis were performed to quantify the accumulated information from genetic association studies investigating the impact of the CYP4F2 rs2108622 (p.V433M) polymorphism on coumarin dose requirement. An additional aim was to explore the contribution of the CYP4F2 variant in comparison with, as well as after stratification for, the VKORC1 and CYP2C9 variants. Thirty studies involving 9,470 participants met prespecified inclusion criteria. As compared with CC-homozygotes, T-allele carriers required an 8.3% (95% confidence interval (CI): 5.6–11.1%; P < 0.0001) higher mean daily coumarin dose than CC homozygotes to reach a stable international normalized ratio (INR). There was no evidence of publication bias. Heterogeneity among studies was present (I2 = 43%). Our results show that the CYP4F2 p.V433M polymorphism is associated with interindividual variability in response to coumarin drugs, but with a low effect size that is confirmed to be lower than those contributed by VKORC1 and CYP2C9 polymorphisms.
A rapid liquid chromatography/tandem mass spectrometry (LC/MS/MS) method was developed for the determination of six cytochrome P450 (CYP) probe substrate metabolites including paracetamol (PAR) for CYP1A2, 4-hydroxytolbutamide (OHTOL) for CYP2C9, 5-hydroxyomeprazole (OHOMe) for CYP2C19, dextrorphan (DEXM) for CYP2D6, 6-hydroxychlorzoxazone (OHCHL) for CYP2E1 and dehydronifedipine (DNIF) for CYP3A4. The triple-quadrupole mass spectrometer was operated in both positive and negative modes, and selective reaction monitoring was used for quantification. The method was validated over the concentration ranges (0.075/0.04/0.05/0.02/0.1/0.0625 microM to 4.8/2.56/3.2/1.28/6.4/4.0 microM) for PAR/OHTOL/OHOME/DEXP/OHCHL/DNIF analytes with acceptable accuracy and precision. The inhibitory effect on the six CYP enzymes has been verified with their known specific inhibitors. This high-throughput inhibition screening approach has been successfully applied to study the inhibitory effects of 18 terpenoids on CYP enzymes. Among them, tanshinone IIA and cryptotanshinone are found to be potent inhibitors to CYP1A2, while artemisinin is a marginal inhibitor to CYP1A2 and glycyrrhetic acid is a weak inhibitor to CYP2C9.
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