Cytochromes P450 2A6, 2E1, and 3A and production of protein-aldehyde adducts in the liver of patients with alcoholic and non-alcoholic liver diseases

Niemelä, Onni; Parkkila, Seppo; Juvonen, Risto O.; Viitala, Katja; Gelboin, Harry V.; Pasanen, Markku

doi:10.1016/s0168-8278(00)80120-8

Cited by 149 publications

(109 citation statements)

References 45 publications

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“…Levels of CYP2E1, CYP3A, and CYP2A6 were elevated in livers of patients with alcoholic and nonalcoholic liver diseases (Niemelä et al, 2000). Induction of CYP2A5 has been suggested to occur in response to liver injury (Su and Ding, 2004).…”

Section: Discussionmentioning

confidence: 99%

“…Chronic ethanol treatment can elevate other P450s besides CYP2E1, e.g., CYP2B or CYP3A (Niemelä et al, 1998). Hepatic levels of CYP2E1, CYP2A6, and CYP3A were elevated in patients with alcoholic and nonalcoholic liver diseases (Niemelä et al, 2000). One study in which ethanol was administered in the drinking water (10% ethanol) for 2 weeks reported that ethanol did not elevate CYP2A5 in DBA mice although pyrazole treatment did (Honkakoski et al, 1988).…”

Section: Introductionmentioning

confidence: 99%

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Ethanol Induction of CYP2A5: Permissive Role for CYP2E1

Zhuge²,

Wu³

et al. 2010

Drug Metab Dispos

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ABSTRACT:CYP2A5 metabolizes xenobiotics and activates hepatocarcinogens, and induction occurs in response to hepatic damage and cellular stress. We evaluated whether ethanol can elevate CYP2A5 and whether CYP2E1 plays a role in the ethanol induction of CYP2A5. Wild-type (WT), CYP2E1 knockout (KO), and CYP2E1 knockin (KI) mice were fed ethanol for 3 weeks. Ethanol increased CYP2E1 and CYP2A5 protein and activity in WT mice but not in the KO mice. Induction of CYP2A5 (and CYP2E1) was restored in the KI mice. Ethanol induction of CYP2A5 occurred only after CYP2E1 was first induced. Immunohistochemical staining revealed that CYP2E1 and CYP2A5 colocalize to the same zones in the liver. Ethanol also elevated CYP2A5 mRNA levels in WT and KI mice but not in KO mice. Induction of CYP2A5 by cadmium was partially decreased in KO mice compared with WT or KI mice. Ethanol elevated CYP2A4 mRNA levels in all mice although the extent of induction was lowest in the KO mice. In summary, ethanol elevated mouse hepatic CYP2A5 levels, which may be of toxicological significance because CYP2A5 metabolizes nicotine and other drugs and activates hepatocarcinogens. Induction of CYP2A5 by ethanol is potentiated by the induction of CYP2E1. We speculate that ethanol induction of CYP2E1 followed by increases in reactive oxygen species and activation of Nrf2 are important steps in the mechanism by which ethanol induces CYP2A5. The possibility that induction of CYP2E1 is permissive for the induction of CYP2A5 may reflect a new contribution by CYP2E1 to the actions of ethanol.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Ethanol Induction of CYP2A5: Permissive Role for CYP2E1

Zhuge²,

Wu³

et al. 2010

Drug Metab Dispos

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“…[61][62][63] It is noteworthy that unlike DNA adducts, there is not a mechanism in place for the repair of adducted proteins. 64 Consequently, protein adducts are persistent until the protein itself is degraded or replaced, which makes them excellent long-term exposure markers.…”

Section: Equation (3)mentioning

confidence: 99%

Covalent Protein Adduction by Drugs of Abuse

Schneider¹

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Recreational abuse of the drugs cocaine, methamphetamine, and morphine continues to be prevalent in the United States of America and around the world. While numerous methods of detection exist for each drug, they are generally limited by the lifetime of the parent drug and its metabolites in the body. However, the covalent modification of endogenous proteins by these drugs of abuse may act as biomarkers of exposure and allow for extension of detection windows for these drugs beyond the lifetime of parent molecules or metabolites in the free fraction. Additionally, existence of covalently bound molecules arising from drug ingestion can offer insight into downstream toxicities associated with each of these drugs.This research investigated the metabolism of cocaine, methamphetamine, and morphine in common in vitro assay systems, specifically focusing on the generation of reactive intermediates and metabolites that have the potential to form covalent protein adducts. Results demonstrated the formation of covalent adduction products between biological cysteine thiols and reactive moieties on cocaine and morphine metabolites. Rigorous mass spectrometric analysis in conjunction with in vitro metabolic activation, pharmacogenetic reaction phenotyping, and computational modeling were utilized to characterize structures and mechanisms of formation for each resultant thiol adduction product. For cocaine, data collected demonstrated the formation of adduction products from a reactive arene epoxide intermediate, designating a novel metabolic pathway for cocaine. In the case of morphine, data expanded on known adduct-forming pathways using sensitive and selective analysis techniques, following the known reactive metabolite, morphinone, and a proposed novel metabolite, morphine quinone methide. Data collected in this study describe novel metabolic events for multiple important drugs of abuse, culminating v in detection methods and mechanistic descriptors useful to both medical and forensic investigators when examining the toxicology associated with cocaine, methamphetamine, and morphine.

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“…The CYP2A6 has also has been found to be induced in fatty, inflamed or cirrhotic livers associated with microorganism infections and harmful alcohol consumption (Kirby et al, 1996;Satarug et al, 1996;Raunio et al, 1998;Niemela et al, 2000;Fisher et al, 2009). The way in which the murine CYP2A5 is regulated during oxidative stress has been described extensively (Raffalli-Mathieu et al, 2002;Glisovic et al, 2003;Abu-Bakar et al, 2004;AbuBakar et al, 2005;Abu-Bakar et al, 2007;Kirby et al, 2011;Lamsa et al, 2012), but little is known about the mechanism(s) by which the human CYP2A6 is regulated under these conditions.…”

Section: Regulation Of Cyp Enzymesmentioning

confidence: 99%

“…Intriguingly, the CAR, C/EBPβ and Oct-1 have been found to be activated by different forms of stress, which include serum starvation stress, endoplasmic reticulum stress, oxidative stress, radiation and DNA damage (Zhao et al, 2000;Jin et al, 2001;Osabe et al, 2009;Meir et al, 2010). Since the CYP2A6 is known to be induced by a variety harmful, structurally unrelated chemicals and pathophysiological conditions (Kirby et al, 1994;Donato et al, 2000;Niemela et al, 2000;De-Oliveira et al, 2006;Kirby et al, 2011;Abu-Bakar et al, 2013), and is highly expressed in the liver , lung, oesophagus, intestinal, oral and bronchial epithelium (Su et al, 1996;Koskela et al, 1999;Janmohamed et al, 2001;Oyama et al, 2006), where the cells typically suffer from high oxygen and chemical exposures, it is possible that the enzyme has a protective function in cells. This assumption is supported by the recent finding that CYP2A6 oxidises bilirubin ─ a potent antioxidant at low intracellular concentration but toxic at high concentration ─ to biliverdin which can be reduced back to bilirubin by biliverdin reductase when there is a depletion of intracellular bilirubin (Abu-Bakar et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Transcriptional regulation of human stress responsive cytochrome P450 2A6 (CYP2A6) by p53

Hu¹

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Human cytochrome P450 (CYP) 2A6 is highly expressed in the liver and the encoding gene is regulated by various stress activated transcription factors, such as the nuclear factor (erythroid-derived 2)-like 2 (Nrf-2). Unlike the other xenobiotic metabolising CYP enzymes (XMEs), CYP2A6 only plays a minor role in xenobiotic metabolism. The CYP2A6 is highly induced by multiple forms of cellular stress conditions, where XMEs expression is normally inhibited. Recent findings suggest that the CYP2A6 plays an important role in regulating BR homeostasis.A computer based sequence analysis on the 3 kb proximate CYP2A6 promoter revealed several putative binding sites for p53, a protein that mediates regulation of antioxidant and apoptosis pathways. In this study, the role of p53 in CYP2A6 gene regulation is demonstrated.The site closest to transcription start site (TSS) is highly homologous with the p53 consensus Replacing the p53RE on the proximal CYP2A6 promoter with a consensus p53RE resulted in an extremely high expression of the recombinant gene regardless of p53 overexpression.While unexpected, this result agrees with the rest of the evidence and supports a model where the stress activated proteins form a compact cluster, assisted by the liver specific HNF-4a for full activity.It has been shown that p53 interacts with Nrf-2 exerting a role in regulating several stress activated genes. Co-transfection of Nrf-2 and p53 together with CYP2A6 promoter in C3A cells demonstrated that the Nrf-2 restrained the p53-mediated CYP2A6 transactivation probably through the "stress cluster" present on the promoter region. Stepwise truncations of the distal CYP2A6 promoter followed by transfection of these promoters into the C3A cells also suggested that the potential suppressor(s) may exist on the "-2253 to -1700bp" and "-688 to-250bp" regions of the promoter.Collectively, the results provide a mechanistic explanation for previous observations that the CYP2A6 is induced by various structurally unrelated toxic insults.ii

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Cytochromes P450 2A6, 2E1, and 3A and production of protein-aldehyde adducts in the liver of patients with alcoholic and non-alcoholic liver diseases

Cited by 149 publications

References 45 publications

Ethanol Induction of CYP2A5: Permissive Role for CYP2E1

Ethanol Induction of CYP2A5: Permissive Role for CYP2E1

Covalent Protein Adduction by Drugs of Abuse

Transcriptional regulation of human stress responsive cytochrome P450 2A6 (CYP2A6) by p53

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