Cytochromes P-450 in human hepatocyte plasma membrane: Recognition by several autoantibodies

Loeper, J; Descatoire, Véronique; Maurice, Michèle; Beaune, Philippe; Belghiti, J; Houssin, D; Ballet, François; Feldmann, Gérard; Guengerich, F. Peter; Pessayre, Dominique

doi:10.1016/0016-5085(93)90853-5

Cited by 149 publications

(90 citation statements)

References 42 publications

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“…CYP2E1, like other xenobiotic metabolizing P450s, is mainly located in the membrane of the endoplasmic reticulum (ER). CYP2E1 has also been detected in other cellular compartments such as the plasma membrane (62)(63)(64). CYP2E1 located at the plasma membrane has been suggested to play a role in the immune mediated hepatotoxicity observed in patients suffering from drug toxicity and ALD (65)(66)(67).…”

Section: Mitochondrial Cyp2e1mentioning

confidence: 99%

CYP2E1 and oxidative liver injury by alcohol

Cederbaum

2008

Free Radical Biology and Medicine

659

534

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Ethanol-induced oxidative stress appears to play a major role in mechanisms by which ethanol causes liver injury. Many pathways have been suggested to contribute to the ability of ethanol to induce a state of oxidative stress. One central pathway appears to be the induction of cytochrome P450 2E1 (CYP2E1) by ethanol. CYP2E1 metabolizes and activates many toxicological substrates, including ethanol, to more reactive, toxic products. Levels of CYP2E1 are elevated under a variety of physiological and pathophysiological conditions, and after acute and chronic alcohol treatment. CYP2E1 is also an effective generator of reactive oxygen species such as the superoxide anion radical and hydrogen peroxide, and in the presence of iron catalysts, produces powerful oxidants such as the hydroxyl radical. This Review Article summarizes some of the biochemical and toxicological properties of CYP2E1, and briefly describes the use of cell lines developed to constitutively express CYP2E1 in assessing the actions of CYP2E1. Possible therapeutic implications for treatment of alcoholic liver injury by inhibition of CYP2E1 or CYP2E1-dependent oxidative stress will be discussed, followed by some future directions which may help to understand the actions of CYP2E1 and its role in alcoholic liver injury.

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Section: Mitochondrial Cyp2e1mentioning

confidence: 99%

CYP2E1 and oxidative liver injury by alcohol

Cederbaum

2008

Free Radical Biology and Medicine

659

534

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“…CYP2D6 is the target of anti-LKM1 autoantibodies (anti-CYP2D6) developed in the type 2 autoimmune hepatitis (Gueguen et al, 1988;Zanger et al, 1988;Kiffel et al, 1989;Manns et al, 1989) and in C viral hepatitis (Parez et al, 1996). Different P450 forms were recognized on the outside face of unpermeabilized hepatocytes by these autoantibodies (Loeper et al, 1990(Loeper et al, , 1993. B-cell epitopes of some of these autoantibodies were characterized by epitope mapping to be sequential or conformational sites located on the cytosol-exposed part of the P450 (for a review, see Lecoeur et al, 1996).…”

mentioning

confidence: 99%

“…CYP2D6, which exhibits an important genetic polymorphism, is involved in the transformation of a great variety of drugs, most of which act on the central nervous system, and is required for metabolic activation of some of these drugs. Its presence at the surface of human hepatocytes (Loeper et al, 1993) and recognition by anti-CYP2D6 autoantibodies directed against a specific cytosol-exposed epitope were demonstrated (Manns et al, 1991;Yamamoto et al, 1993). This isoform was chosen as a model to investigate catalytic competence of PM P450s.…”

mentioning

confidence: 99%

Yeast Expressed Cytochrome P450 2D6 (CYP2D6) Exposed on the External Face of Plasma Membrane Is Functionally Competent

et al. 1998

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CYP2D6, a xenobiotic metabolizing cytochrome P450 (P450), was found to be present in significant amount on the outer face of cell plasma membrane in addition to the regular microsomal location. Present work demonstrates that this external P450 is catalytically competent and that activity is supported by NADPH-P450 reductase present on the inner face of plasma membrane. Purified plasma membranes from yeast expressing CYP2D6 sustained NADPH-and cumene hydroperoxide-dependent dextromethorphan demethylation and NADPH-cytochrome c activity confirming previous observations in human hepatocytes. CYP2D6 found on the outside of plasma membrane (by differential immuno-inhibition and acidic shift assays on transformed spheroplasts) was catalytically competent at the cell surface for NADPH-supported activities. Anti-yeast P450-reductase antibodies inhibited neither CYP2D6 nor P450-reductase activities upon incubation with intact spheroplasts. In contrast, both activities were inhibited on isolated plasma membrane fragments. This highly suggested a cytosolic-orientation of the plasma membrane P450-reductase. This finding was confirmed by immunostaining in confocal microscopy. Finally, gene deletion of P450-reductase caused a complete loss of plasma membrane NADPH-supported CYP2D6 activity, which suggests that the reductase participates to some degree in the transmembrane electron transfer chain. This work illustrates that the outside-exposed plasma membrane CYP2D6 is active and may play an important metabolic role.

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“…Because CYP450 enzymes are located in hepatocytes [ 36 ] and functionalized MWCNTs (f-MWCNTs) are also internalized by hepatocytes, the next part of this study investigated how MWCNTs interact with CYP450 enzymes. Surface modifi cations should offer MWCNTs different physiochemical properties.…”

Section: Functionalized Mwcnts Bind Cyp450 Enzymes In Human Liver Micmentioning

confidence: 99%

“…[ 24,35 ] Because the CYP450 enzymes responsible for drug metabolism primarily reside in hepatocytes in the liver, [ 36 ] we fi rst investigated whether MWCNTs accumulated in the liver entered hepatocytes. Two hours after i.v.…”

Section: Mwcnts Enter Hepatocytesmentioning

confidence: 99%

Modulation of Carbon Nanotubes' Perturbation to the Metabolic Activity of CYP3A4 in the Liver

Zhang

Wang

Liu

et al. 2015

Adv Funct Materials

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The liver plays an important role in metabolizing foreign materials, such as drugs. The high accumulation of carbon nanotubes and other hydrophobic nanoparticles in the liver has raised concerns that nanoparticles may interfere with liver metabolic function. We report here that carbon nanotubes enter hepatic cells after intravenous introduction and interact with CYP enzymes, including CYP3A4. Surface chemical modifications alter the carbon nanotubes' interactions with CYP450 enzymes in human liver microsomes. They enhance, inhibit, or have no effect on the enzymatic function of CYP3A4. Using a cheminformatics analysis, certain chemical structures are identified on the surface of the carbon nanotubes that induce an enzyme inhibitory effect or prevent disruption of CYP3A4 enzymes.

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Cytochromes P-450 in human hepatocyte plasma membrane: Recognition by several autoantibodies

Cited by 149 publications

References 42 publications

CYP2E1 and oxidative liver injury by alcohol

CYP2E1 and oxidative liver injury by alcohol

Yeast Expressed Cytochrome P450 2D6 (CYP2D6) Exposed on the External Face of Plasma Membrane Is Functionally Competent

Modulation of Carbon Nanotubes' Perturbation to the Metabolic Activity of CYP3A4 in the Liver

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