Physiological Content and Intrinsic Activities of 10 Cytochrome P450 Isoforms in Human Normal Liver Microsomes

Zhang, Haifeng; Wang, Huanhuan; Gao, Na; Wei, Junying; Tian, Xin; Zhao, Yan; Fang, Yan; Zhou, Jun; Wen, Qiang; Gao, Jie; Zhang, Yang-Jun; Qian, Xiaohong; Qiao, Huan

doi:10.1124/jpet.116.233635

Cited by 75 publications

(75 citation statements)

References 38 publications

(49 reference statements)

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“…As the organ most directly involved in metabolizing and detoxifying environmental carcinogens, the liver is continually exposed to harmful chemicals and their metabolites which can cause chronic liver injury, inflammation, and hepatofibrosis that may eventually culminate in the formation of HCC . As an enzyme directly involved in procarcinogen metabolism and activation, cytochrome P450 2E1 (CYP2E1) has been of interest to us; moreover, we previously found that there is considerable variability in its activity between individuals . It should be noted that many known industrial chemicals and environmental toxicants, as well as procarcinogens (eg, nitrosamines, benzene, and vinyl chloride) are metabolized by CYP2E1 .…”

Section: Introductionmentioning

confidence: 99%

From hepatofibrosis to hepatocarcinogenesis: Higher cytochrome P450 2E1 activity is a potential risk factor

Gao

Wang

et al. 2018

Molecular Carcinogenesis

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Hepatofibrosis is an important susceptibility factor for hepatocarcinogenesis. However, only a handful of cases of hepatofibrosis will develop into hepatocellular carcinoma (HCC). As cytochrome P450 2E1 (CYP2E1) is involved in the metabolism and activation of many known environmental toxicants and procarcinogens, this enzyme may play a role in the development of hepatocarcinogenesis subsequent to hepatofibrosis. Herein, we evaluated whether higher CYP2E1 activity is a risk factor for the development of hepatocarcinogenesis from hepatofibrosis. CYP2E1 activity in fibrotic tissues from 72 HCC patients and in normal liver tissues from 59 control subjects was determined along with the severity of hepatofibrosis in hepatocarcinogenesis patients. Similarly, using a rat diethylnitrosamine-induced hepatocarcinogenesis model, CYP2E1 activity at the hepatofibrosis and hepatocarcinogenesis stages was determined, the correlation between CYP2E1 activity at the hepatofibrosis stage and hepatocarcinogenesis was explored, and the impact of inhibition of CYP2E1 activity on hepatocarcinogenesis was studied. The results showed that while CYP2E1 activity in HCC patients with underlying hepatofibrosis was increased, the severity of hepatofibrosis did not correlate with CYP2E1 activity. In the rat hepatocarcinogenesis model, unexpectedly, CYP2E1 activity was found to decrease from hepatofibrosis to hepatocarcinogenesis. Importantly, however, hepatofibrotic rats with higher CYP2E1 activity developed a more severe form of HCC. Moreover, inhibition of CYP2E1 activity could decrease the occurrence and development of HCC in rats. In conclusion, higher CYP2E1 activity may be a risk factor for hepatocarcinogenesis from hepatofibrosis, which raises the possibility of screening patients with hepatofibrosis for CYP2E1 activity to better estimate their risk for hepatocarcinogenesis.

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Section: Introductionmentioning

confidence: 99%

From hepatofibrosis to hepatocarcinogenesis: Higher cytochrome P450 2E1 activity is a potential risk factor

Gao

Wang

et al. 2018

Molecular Carcinogenesis

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“…Cytochrome P450 3As (CYP3As) represent ~25% and 80% of all CYP450s expressed in human liver and intestines, respectively . CYP3As play a critical role in the metabolism of approximately half of all marketed drugs .…”

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confidence: 99%

Use of 4β‐Hydroxycholesterol Plasma Concentrations as an Endogenous Biomarker of CYP3A Activity: Clinical Validation in Individuals With Type 2 Diabetes

Gravel

Chiasson

Gaudette

et al. 2019

Clin Pharma and Therapeutics

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The relevance of endogenous 4β‐hydroxycholesterol (4β‐OHC) plasma concentrations or of the 4β‐OHC/total cholesterol concentration ratio (4β‐OHC ratio) as surrogate markers of cytochrome P450 3A (CYP3A) activity was evaluated in individuals with (n = 38) or without (n = 35) type 2 diabetes (T2D). Midazolam was used as a comparator to validate exploratory measures of phenotypic CYP3A activity. Metabolic ratios of orally administered midazolam in nondiabetic and diabetic populations correlated significantly with 4β‐OHC (rs = 0.64 and 0.48; P ≤ 0.003) and 4β‐OHC ratio (rs = 0.69 and 0.46; P ≤ 0.003), respectively. Activity of CYP3A was lower in the T2D population compared with nondiabetic subjects; this decrease was reflected in 4β‐OHC concentrations (24.33 vs. 12.58 ng/mL; P < 0.0001) and 4β‐OHC ratio (0.13 vs. 0.09 (× 104); P < 0.0002). These results suggest that 4β‐OHC should be considered as a valid, convenient, and easy to use endogenous biomarker of CYP3A activity in patients.

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“…However, in spite of the initial premise that the cumulative properties of this ensemble represent a simple aggregate of the properties of the constituting enzymes, there is a growing body of evidence that suggests important non-additive contribution of mutual functional effects of multiple P450 species. Thus, it becomes increasingly evident that the catalytic properties of the ensemble of drug-metabolizing cytochromes P450 cannot be ascertained from a simple summation of the properties of the contributing P450 species (4–6). …”

mentioning

confidence: 99%

“…Functional effects of interactions of CYP2D6 with ethanol-inducible CYP2E1, the most abundant P450 enzyme in human liver (6), are of special interest due to the role played by CYP2D6 in the metabolism of psychoactive agents including those known of clinically important interactions with alcohol (24). In particular, the role played by CYP2D6 in the metabolism of MDMA (ecstasy) (25–27) suggests a potential involvement of CYP2D6-CYP2E1 interactions in exacerbation of hepato- and neurotoxicity of this widespread drug of abuse by alcohol consumption (28).…”

mentioning

confidence: 99%

Toward a systems approach to the human cytochrome P450 ensemble: interactions between CYP2D6 and CYP2E1 and their functional consequences

Davydov

Davydova

Rodgers

et al. 2017

Biochemical Journal

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Functional cross-talk among human drug-metabolizing cytochromes P450 through their association is a topic of emerging importance. Here we studied the interactions of human CYP2D6, a major metabolizer of psychoactive drugs, with one of the most prevalent human P450 enzymes, ethanol-inducible CYP2E1. Detection of P450-P450 interactions was accomplished through luminescence resonance energy transfer (LRET) between labeled proteins incorporated into human liver microsomes and the microsomes of insect cells containing NADPH-cytochrome P450 reductase. The potential of CYP2D6 to form oligomers in the microsomal membrane is among the highest observed with human cytochromes P450 studied up to date. We also observed the formation of heteromeric complexes of CYP2D6 with CYP2E1 and CYP3A4, and found a significant modulation of these interactions by MDMA, a widespread drug of abuse metabolized by CYP2D6. Our results demonstrate an ample alteration of the catalytic properties of CYP2D6 and CYP2E1 caused by their association. In particular, we demonstrated that pre-incubation of microsomes containing co-incorporated CYP2D6 and CYP2E1 with CYP2D6-specific substrates resulted in considerable time-dependent activation of CYP2D6, which presumably occurs via a slow substrate-induced reorganization of CYP2E1-CYP2D6 heterooligomers. Furthermore, we demonstrated that the formation of heteromeric complexes between CYP2E1 and CYP2D6 affects the stoichiometry of futile cycling and substrate oxidation by CYP2D6 by means of decreasing the electron leakage through the peroxide-generating pathways. Our results further emphasize the role of P450-P450 interactions in regulatory cross-talk in human drug-metabolizing ensemble and suggest a role of interactions of CYP2E1 with CYP2D6 in pharmacologically important instances of alcohol-drug interactions.

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Physiological Content and Intrinsic Activities of 10 Cytochrome P450 Isoforms in Human Normal Liver Microsomes

Cited by 75 publications

References 38 publications

From hepatofibrosis to hepatocarcinogenesis: Higher cytochrome P450 2E1 activity is a potential risk factor

From hepatofibrosis to hepatocarcinogenesis: Higher cytochrome P450 2E1 activity is a potential risk factor

Use of 4β‐Hydroxycholesterol Plasma Concentrations as an Endogenous Biomarker of CYP3A Activity: Clinical Validation in Individuals With Type 2 Diabetes

Toward a systems approach to the human cytochrome P450 ensemble: interactions between CYP2D6 and CYP2E1 and their functional consequences

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