cAMP Mediated Upregulation of CYP2A5 in Mouse Hepatocytes

Viitala, Pirkko; Posti, Katja; Lindfors, Aija; Pelkonen, Olavi; Raunio, Hannu

doi:10.1006/bbrc.2000.4195

Cited by 24 publications

(17 citation statements)

References 31 publications

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“…CYP2A5 is shown to be induced by fasting, 43 and by glucagon through a cyclic adenosine monophosphate (cAMP)-mediated pathway, 44 suggesting that energy supply could be involved in CYP2A5 regulation also in cultured hepatocytes. Both USF and ARNT have been linked to the regulation of glucose and lipid metabolism.…”

Section: Discussionmentioning

confidence: 99%

Aryl Hydrocarbon Receptor Nuclear Translocator and Upstream Stimulatory Factor Regulate Cytochrome P450 2a5 Transcription through a Common E-box Site

Arpiainen

Lämsä

Pelkonen

et al. 2007

Journal of Molecular Biology

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Section: Discussionmentioning

confidence: 99%

Aryl Hydrocarbon Receptor Nuclear Translocator and Upstream Stimulatory Factor Regulate Cytochrome P450 2a5 Transcription through a Common E-box Site

Arpiainen

Lämsä

Pelkonen

et al. 2007

Journal of Molecular Biology

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“…During these conditions, glucagon stimulates cell surface receptors and triggers an increase in intracellular cAMP. Stimulation of cAMP signal transduction by glucagon and isoproterenol has been shown to markedly increase CYP2A5 activity [24]. Increased cAMP upregulates transcriptional coactivators that then interact with HNF-4 to positively regulate target gene transcription [67].…”

Section: Transcriptional Regulation Of Cyp2a5mentioning

confidence: 99%

“…cAMP levels such as dibutyryl-cAMP, glucagon, forskolin, and isoproterenol [24]. In addition, CYP2A5 is induced by TCPOBOP [25], DTTox [26], rifampicin [27], isothiocyanate [21] and buthionine sulfoximine [26].…”

Section: Introductionmentioning

confidence: 99%

CYP2A5 Induction and Hepatocellular Stress: An Adaptive Response to Perturbations of Heme Homeostasis

Kirby

Nichols²,

Antenos

2011

CDM

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Unlike most cytochrome P450 (CYP) enzymes, murine hepatic CYP2A5 is induced during pathological conditions that result in liver injury including hepatotoxicity mediated by xenobiotics, hepatitis caused by various microbial agents and liver neoplasia. Since CYP2A5 metabolizes various important xenobiotics including nicotine and pro-carcinogens such as nitrosamines and aflatoxin B(1), altered gene expression could affect tobacco addiction, hepatotoxicity and hepatocarcinogenesis. This article synthesizes the current knowledge concerning hepatic expression of Cyp2a5 including the transcriptional and post-transcriptional regulatory mechanisms, pathophysiological conditions associated with enzyme induction such as oxidative and endoplasmic reticulum stress and altered lipid and energy homeostasis as well as the known exogenous and putative endogenous substrates. Knowledge of the stimuli responsible for the unique overexpression of CYP2A5 during liver injury may provide clues to a functional role for this enzyme and the impact of variable CYP2A5 expression on xenobiotic metabolism and toxicity, disease development and the adaptive response to hepatocellular stress.

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“…Glucagon prevents the expression of pi class GSTs in primary cultured hepatocytes (Kim et al, 2003a). Table 1 shows the insulin-and glucagon-mediated regulation of the activity and/or expression of hepatic drug metabolizing enzymes genes and protein such as CYP2B, CYP2E1, CYP2A5, GCL, GST alpha class, GST pi class, UGT and mEH (De Waziers et al, 1995;Constantopoulos and Matsaniotis, 1978;Ricci and Fevery, 1988;Viitala et al, 2001;Carrillo et al, 1995;Iber et al, 2001;Novak, 1997 and1999a;Woodcroft et al, 2002;Lu et al, 1991 andKim et al, 2003a and2003b;Truong et al, 2005). These results show that changes in drug-metabolizing enzyme gene expression or protein levels may be attributed to alterations in insulin levels.…”

Section: Generalmentioning

confidence: 99%

The role of intracellular signaling in insulin-mediated regulation of drug metabolizing enzyme gene and protein expression

Kim

Novak

2007

Pharmacology & Therapeutics

143

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Endogenous factors, including hormones, growth factors and cytokines, play an important role in the regulation of hepatic drug metabolizing enzyme expression in both physiological and pathophysiological conditions. Alterations of hepatic drug metabolizing enzymes gene and protein expression, observed in diabetes, fasting, obesity, protein-calorie malnutrition and long-term alcohol consumption alters the metabolism of xenobiotics, including procarcinogens, carcinogens, toxicants, and therapeutic agents and may also impact the efficacy and safety of therapeutic agents, as well as result in drug-drug interactions. Although the mechanisms by which xenobiotics regulate drug metabolizing enzymes have been studied intensively, less is known regarding the cellular signaling pathways and components which regulate drug metabolizing enzyme gene and protein expression in response to hormones and cytokines. Recent findings, however, have revealed that several cellular signaling pathways are involved in hormone-and growth factor-mediated regulation of drug metabolizing enzymes. Our laboratory, and others, have demonstrated that insulin and growth factors regulate drug metabolizing enzyme gene and protein expression, including cytochromes P450, glutathione S-transferases and microsomal epoxide hydrolase, through receptors which are members of the large receptor tyrosine kinase family, and by downstream effectors such as phosphatidylinositol 3-kinase, the mitogen activated protein kinase, Akt/protein kinase B, mTOR, and the p70S6 kinase. Here, we review current knowledge of the signaling pathways implicated in regulation of drug metabolizing enzyme gene and protein expression in response to insulin and growth factors, with the goal of increasing our understanding of how chronic disease affects these signaling pathways, components, and ultimately gene expression and translational control.

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cAMP Mediated Upregulation of CYP2A5 in Mouse Hepatocytes

Cited by 24 publications

References 31 publications

Aryl Hydrocarbon Receptor Nuclear Translocator and Upstream Stimulatory Factor Regulate Cytochrome P450 2a5 Transcription through a Common E-box Site

Aryl Hydrocarbon Receptor Nuclear Translocator and Upstream Stimulatory Factor Regulate Cytochrome P450 2a5 Transcription through a Common E-box Site

CYP2A5 Induction and Hepatocellular Stress: An Adaptive Response to Perturbations of Heme Homeostasis

The role of intracellular signaling in insulin-mediated regulation of drug metabolizing enzyme gene and protein expression

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