Regulation of the cytochrome P450 2A genes

Su, Ting; Ding, Xinxin

doi:10.1016/j.taap.2003.11.029

Cited by 89 publications

(91 citation statements)

References 106 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). Results in the current report show that feeding mice an ethanol liquid diet results in an increase in CYP2A5 levels and catalytic activity compared with those in pair-fed dextrose controls.…”

Section: Discussionsupporting

confidence: 45%

“…The female SV129 wild-type mice were purchased from Charles River Laboratories, Inc. (Wilmington, MA). Depending on the strain, female mice express much higher levels of CYP2A4 than male mice, whereas CYP2A5 is highly expressed in both male and female mice (Honkakoski and Negishi, 1997;Su and Ding, 2004). All mice were housed in temperaturecontrolled animal facilities with 12-h light/dark cycles and were permitted consumption of tap water and Purina standard chow ad libitum until being fed the liquid diets.…”

Section: Methodsmentioning

confidence: 99%

“…Mouse CYP2A5 and its human ortholog CYP2A6 metabolize several important xenobiotics including nicotine, coumarin, cotinine, testosterone, aflatoxin B1, and nitrosamines (Su and Ding, 2004). CYP2A5 is expressed in many tissues with high levels found in the respiratory tract, liver, and kidney.…”

Section: Introductionmentioning

confidence: 99%

“…Pyrazole, widely used as an inhibitor of alcohol dehydrogenase and of ethanol metabolism (Goldberg and Rydberg, 1969), induces CYP2A5 largely by a post-transcriptional mechanism involving stabilization of the CYP2A5 mRNA (Juvonen et al, 1985;Nichols and Kirby, 2008). Recent studies have indicated a role for cellular redox status and possible activation of stress-related transcription factors in activation of CYP2A5 (Gilmore and Kirby, 2004;Su and Ding, 2004;Abu-Bakar et al, 2007;Lämsä et al, 2010). For example, treatment of hepatocytes with menadione, a redox cycling agent, elevated CYP2A5 expression (Gilmore and Kirby, 2004).…”

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: Discussionsupporting

confidence: 45%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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“…The mechanism of the unique regulation of Cyp2a5 during these conditions is unclear and remains to be investigated. The one demonstrated mechanism that is common in these conditions is, in part, oxidative stress (Kirby et al, 1994b;Chomarat et al, 1997;Nebert et al, 2000;Cheung et al, 2003;Gilmore et al, 2003;Gilmore and Kirby, 2004;Su and Ding, 2004;Weng et al, 2005;Chen and Siddiqui, 2007;Fisher et al, 2009;De-Oliveira et al, 2010). Furthermore, these conditions appear to be associated with increased serum bilirubin levels (Bonacini, 2004;Malaguarnera et al, 2005;Richardson et al, 2006b;Hansen, 2010).…”

Section: Pathophysiological States Associated With Cyp2a5mentioning

confidence: 99%

Cytochrome P450 2A5 and bilirubin: Mechanisms of gene regulation and cytoprotection

Kim

Antenos

Squires

et al. 2013

Toxicology and Applied Pharmacology

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Murine cytochrome P450 2A5 (CYP2A5) is an interesting enzyme for its unique regulation and its involvement in liver injury caused by various well-known pathological conditions or hepatotoxins. It has been reported that CYP2A5 is upregulated following exposure to chemical hepatotoxins and during pathophysiological conditions in which the levels of most Cytochrome P450s are either unchanged or down-regulated. Recently bilirubin has been identified as the first endogenous substrate for CYP2A5 and it has been suggested that CYP2A5 plays a major role in bilirubin clearance as an alternative mechanism to BR conjugation by UGT1A1. This study investigated the mechanisms of gene regulation and cytoprotective role of CYP2A5 in response to bilirubin treatment in liver. Our results demonstrate that bilirubin induces CYP2A5 expression at the mRNA and protein levels by increasing CYP2A5 transcription via a mechanism that involves Nrf2 activation. Furthermore, our results suggest that induced CYP2A5 plays a cytoprotective role against bilirubin toxicity by directly lowering the cellular levels of bilirubin and by inhibiting caspase-3 activation.iii ACKNOWLEDGEMENTS

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CYP450 Enzymes in Drug Discovery and Development: An Overview

Das

Prakash

2012

Encyclopedia of Drug Metabolism and Interactions

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Cytochrome P450 enzymes play an important role in the metabolism of foreign molecules (drugs and environmental chemicals) and endogenous compounds. This large enzyme family facilitates to eliminate xenobiotics from the body and catalyzes the catabolism of endogenous compounds for their physiological functions. In this chapter, we describe the most recent advances in our knowledge and application of P450 enzymes in drug discovery and development with particular emphasis on their involvement in the metabolism of drugs. In addition, we have also summarized the basic catalytic activity of this enzyme family, commonly observed biotransformation in drugs, the species and ethnic variation in the expression of P450 enzymes, and the tools used to extrapolate metabolism and toxicity in animals to humans.

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Regulation of the cytochrome P450 2A genes

Cited by 89 publications

References 106 publications

Ethanol Induction of CYP2A5: Permissive Role for CYP2E1

Ethanol Induction of CYP2A5: Permissive Role for CYP2E1

Cytochrome P450 2A5 and bilirubin: Mechanisms of gene regulation and cytoprotection

CYP450 Enzymes in Drug Discovery and Development: An Overview

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