CYP2E1 and risk of chemically mediated cancers

Trafalis, Dimitrios T.; Panteli, Eleftheria S; Grivas, Anastasios; Tsigris, Christos; Karamanakos, Petros N

doi:10.1517/17425250903540238

Cited by 58 publications

(38 citation statements)

References 90 publications

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“…This CYP enzyme is also inducible [47]. In the current work, a significantly lower chlorzoxazone 6-hydroxylase activity (CLint) was observed in Chinese HLM than Caucasian HLM.…”

Section: Discussionmentioning

confidence: 50%

“…CYP2D6 is not known to be significantly inducible and the genetic variation contributes largely to the interindividual and interethnic variations in metabolic activity [47]. The appearance of poor metabolizers is lower in Asians (~1%) than Caucasians (5-10%), whereas enzyme activity is lower in Asian extensive metabolizers than in Caucasian counterparts.…”

Section: Discussionmentioning

confidence: 99%

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Metabolic capabilities of cytochrome P450 enzymes in Chinese liver microsomes compared with those in Caucasian liver microsomes

Yang

Niu

et al. 2012

Brit J Clinical Pharma

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• The mean catalytic activities of CYP1A2, CYP2A6, CYP2D6, CYP2E1 and CYP3A4 in human liver microsomes (HLM) of Japanese origin were found to be lower than the corresponding mean values of Caucasian HLM, but the distribution patterns of data in these studies were not well addressed.• Interindividual variations in metabolic activities of Chinese HLM samples were reported for CYP1A2, CYP2C9, CYP2D6 and CYP3A4, but little is known about the difference in CYP activities between Chinese and Caucasian HLM samples.• The vast majority of the preceding studies were based on the measurement of metabolite formation rates at a certain fixed substrate concentration, rather than enzyme kinetic analyses.WHAT THIS STUDY ADDS• Significant differences in metabolic capability were observed for CYP1A2, CYP2C9, CYP2C19 and CYP2E1 with the median values lower for the Chinese HLM samples vs. the Caucasian samples, which were associated with differences in Michaelis constant or maximum velocity.• Despite negligible differences in metabolic capability for CYP2A6, CYP2B6, CYP2C8, CYP2D6 and CYP3A, Michaelis constant of CYP2B6 appeared to have a significant ethnic difference.AIM The most common causes of variability in drug response include differences in drug metabolism, especially when the hepatic cytochrome P450 (CYP) enzymes are involved. The current study was conducted to assess the differences in CYP activities in human liver microsomes (HLM) of Chinese or Caucasian origin.METHODS The metabolic capabilities of CYP enzymes in 30 Chinese liver microsomal samples were compared with those of 30 Caucasian samples utilizing enzyme kinetics. Phenacetin O‐deethylation, coumarin 7‐hydroxylation, bupropion hydroxylation, amodiaquine N‐desethylation, diclofenac 4′‐hydroxylation (S)‐mephenytoin 4′‐hydroxylation, dextromethorphan O‐demethylation, chlorzoxazone 6‐hydroxylation and midazolam 1′‐hydroxylation/testosterone 6β‐hydroxylation were used as probes for activities of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A, respectively. Mann‐Whitney U test was used to assess the differences.RESULTS The samples of the two ethnic groups were not significantly different in cytochrome‐b5 concentrations but were significantly different in total CYP concentrations and NADPH‐P450 reductase activity (P < 0.05). Significant ethnic differences in intrinsic clearance were observed for CYP1A2, CYP2C9, CYP2C19 and CYP2E1; the median values of the Chinese group were 54, 58, 26, and 35% of the corresponding values of the Caucasian group, respectively. These differences were associated with differences in Michaelis constant or maximum velocity. Despite negligible difference in intrinsic clearance, the Michaelis constant of CYP2B6 appeared to have a significant ethnic difference. No ethnic difference was observed for CYP2A6, CYP2C8, CYP2D6 and CYP3A.CONCLUSIONS These data extend our knowledge on the ethnic differences in CYP enzymes and will have implications for drug discovery and drug therapy for patients from different ethnic origins.

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“…This CYP enzyme is also inducible [47]. In the current work, a significantly lower chlorzoxazone 6-hydroxylase activity (CLint) was observed in Chinese HLM than Caucasian HLM.…”

Section: Discussionmentioning

confidence: 50%

Section: Discussionmentioning

confidence: 99%

Metabolic capabilities of cytochrome P450 enzymes in Chinese liver microsomes compared with those in Caucasian liver microsomes

Yang

Niu

et al. 2012

Brit J Clinical Pharma

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“…This "sandwich" culture approach is not required with HepaRG cells, but the high concentrations of DMSO that are used to differentiate HepaRG cells (Gripon et al, 2002) can also inhibit some P450 enzymes (e.g., CYP2E1). CYP2E1 is involved in many examples of metabolically activated toxicity (i.e., acetaminophen), and overlay of cryo-HepaRG may support more mature differentiation and require lower DMSO levels (Easterbrook et al, 2001;Trafalis et al, 2010). Recent reports have used HepaRG cells in three-dimensional culture configurations and observed similar increases in metabolic capacity/longevity.…”

Section: Discussionmentioning

confidence: 99%

Contextualizing Hepatocyte Functionality of Cryopreserved HepaRG Cell Cultures

Jackson

Chamberlain

et al. 2016

Drug Metabolism and Disposition

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Over the last decade HepaRG cells have emerged as a promising alternative to primary human hepatocytes (PHH) and have been featured in over 300 research publications. Most of these reports employed freshly differentiated HepaRG cells that require timeconsuming culture (∼28 days) for full differentiation. Recently, a cryopreserved, predifferentiated format of HepaRG cells (termed here "cryo-HepaRG") has emerged as a new model that improves global availability and experimental flexibility; however, it is largely unknown whether HepaRG cells in this format fully retain their hepatic characteristics. Therefore, we systematically investigated the hepatocyte functionality of cryo-HepaRG cultures in context with the range of interindividual variation observed with PHH in both sandwich-culture and suspension formats. These evaluations uncovered a novel adaptation period for the cryo-HepaRG format and demonstrated the impact of extracellular matrix on cryo-HepaRG functionality. Pharmacologically important drug-metabolizing alleles were genotyped in HepaRG cells and poor metabolizer alleles for CYP2D6, CYP2C9, and CYP3A5 were identified and consistent with higher frequency alleles found in individuals of Caucasian decent. We observed liver enzyme inducibility with aryl hydrocarbon receptor, constitutive androstane receptor (CAR), and pregnane X receptor activators comparable to that of sandwich-cultured PHH. Finally, we show for the first time that cryo-HepaRG supports proper CAR cytosolic sequestration and translocation to hepatocyte nuclei in response to phenobarbital treatment. Taken together, these data reveal important considerations for the use of this cell model and demonstrate that cryo-HepaRG are suitable for metabolism and toxicology screening.

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“…Interindividual variability in the expression and functional activity of CYP2E1 has been observed (Neafsey et al 2009 ) and genetic polymorphisms in CYP2E1 have been linked to altered susceptibility to several diseases (Trafalis et al 2010 ) . Also, chronic exposure to CYP2E1 inducers, such as ethanol, isoniazid, various solvents and chemicals, also increase the probability of developing malignancy, especially for carriers of certain CYP2E1 alleles (Trafalis et al 2010 ) .…”

Section: Importance Of Cyp2e1 In Health and Diseasementioning

confidence: 99%

“…Also, chronic exposure to CYP2E1 inducers, such as ethanol, isoniazid, various solvents and chemicals, also increase the probability of developing malignancy, especially for carriers of certain CYP2E1 alleles (Trafalis et al 2010 ) .…”

Section: Importance Of Cyp2e1 In Health and Diseasementioning

confidence: 99%

Cytochrome P450 2E1: Its Clinical Aspects and a Brief Perspective on the Current Research Scenario

Dey

2013

Subcellular Biochemistry

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Research on Cytochrome P450 2E1 (CYP2E1), a key enzyme in alcohol metabolism has been very well documented in literature. Besides the involvement of CYP2E1 in alcohol metabolism as illustrated through the studies discussed in the chapter, recent studies have thrown light on several other aspects of CYP2E1 i.e. its extrahepatic expression, its involvement in several diseases and pathophysiological conditions; and CYP2E1 mediated carcinogenesis and modulation of drug efficacy. Studies involving these interesting facets of CYP2E1 have been discussed in the chapter focusing on the recent observations or ongoing studies illustrating the crucial role of CYP2E1 in disease development and drug metabolism.

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CYP2E1 and risk of chemically mediated cancers

Abstract: Genetic screening for CYP2E1 'carcinogenic' polymorphisms and CYP2E1 phenotype determination of susceptible subjects, as well as the development of effective CYP2E1 inhibitors, could be a future perspective towards prevention of CYP2E1-mediated cancers.

Cited by 58 publications

References 90 publications

Metabolic capabilities of cytochrome P450 enzymes in Chinese liver microsomes compared with those in Caucasian liver microsomes

Metabolic capabilities of cytochrome P450 enzymes in Chinese liver microsomes compared with those in Caucasian liver microsomes

Contextualizing Hepatocyte Functionality of Cryopreserved HepaRG Cell Cultures

Cytochrome P450 2E1: Its Clinical Aspects and a Brief Perspective on the Current Research Scenario

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