Effects of lipopolysaccharide-stimulated inflammation and pyrazole-mediated hepatocellular injury on mouse hepatic Cyp2a5 expression

Gilmore, Wendy; Hartmann, Georgy; Piquette-Miller, Micheline; Marriott, Jason J.A.; Kirby, Gordon M.

doi:10.1016/s0300-483x(02)00581-4

Cited by 39 publications

(45 citation statements)

References 50 publications

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“…Significantly elevated levels of CYP2A6 enzymatic activity have been reported in patients with hepatitis, primary biliary cirrhosis, and alcoholic cirrhosis (Kirby et al, 1996;Bechtel et al, 2000;Lelouët et al, 2001). In addition, induction of CYP2A5, the mouse ortholog of human CYP2A6, has been shown to be induced during oxidative injury to the endoplasmic reticulum, as well as during altered redox status (Gilmore et al, 2003;Nichols and Kirby, 2008). It is well documented that oxidative stress occurs in NAFLD patients, as shown by NASH patients who show significantly increased systemic levels of lipid peroxidation products (Chalasani et al, 2004;Videla et al, 2004).…”

Section: Fisher Et Almentioning

confidence: 99%

Hepatic Cytochrome P450 Enzyme Alterations in Humans with Progressive Stages of Nonalcoholic Fatty Liver Disease

et al. 2009

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ABSTRACT:Members of the cytochrome P450 (P450) enzyme families CYP1, CYP2, and CYP3 are responsible for the metabolism of approximately 75% of all clinically relevant drugs. With the increased prevalence of nonalcoholic fatty liver disease (NAFLD), it is likely that patients with this disease represent an emerging population at significant risk for alterations in these important drug-metabolizing enzymes. The purpose of this study was to determine whether three progressive stages of human NALFD alter hepatic P450 expression and activity. Microsomes isolated from human liver samples diagnosed as normal, n ‫؍‬ 20; steatosis, n ‫؍‬ 11; nonalcoholic steatohepatitis (NASH) (fatty liver), n ‫؍‬ 10; and NASH (no longer fatty), n ‫؍‬ 11 were analyzed for P450 mRNA, protein, and enzyme activity. Microsomal CYP1A2, CYP2D6, and CYP2E1 mRNA levels were decreased with NAFLD progression, whereas CYP2A6, CYP2B6, and CYP2C9 mRNA expression increased. Microsomal protein expression of CYP1A2, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 tended to decrease with NAFLD progression. Likewise, functional activity assays revealed decreasing trends in CYP1A2 (p ‫؍‬ 0.001) and CYP2C19 (p ‫؍‬ 0.05) enzymatic activity with increasing NAFLD severity. In contrast, activity of CYP2A6 (p ‫؍‬ 0.001) and CYP2C9 (diclofenac, p ‫؍‬ 0.0001; tolbutamide, p ‫؍‬ 0.004) was significantly increased with NAFLD progression. Increased expression of proinflammatory cytokines tumor necrosis factor ␣ and interleukin 1␤ was observed and may be responsible for observed decreases in respective P450 activity. Furthermore, elevated CYP2C9 activity during NAFLD progression correlated with elevated hypoxia-induced factor 1␣ expression in the later stages of NAFLD. These results suggest that significant and novel changes occur in hepatic P450 activity during progressive stages of NAFLD.

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Section: Fisher Et Almentioning

confidence: 99%

Hepatic Cytochrome P450 Enzyme Alterations in Humans with Progressive Stages of Nonalcoholic Fatty Liver Disease

et al. 2009

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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%

“…Furthermore, these conditions appear to be associated with increased serum bilirubin levels (Bonacini, 2004;Malaguarnera et al, 2005;Richardson et al, 2006b;Hansen, 2010). (Pellinen et al, 1993) Chloroform Anesthetic/Teflon (Camus et al, 1996) Cocaine Topical anesthetic (Pellinen et al, 1994a(Pellinen et al, , 1994b) Ethanol Fuel, beverage, and antiseptic (Lu et al, 2010) Phenobarbital Barbiturate and anticonvulsant (Hahnemann et al, 1992;Salonpää et al, 1994) Pyrazole Precursor for various medicines (Juvonen et al, 1985;Nichols and Kirby, 2008 (Cai et al, 2002) Buthionine sulfoximine Drug used in chemotherapy to reduce levels of glutathione (Gilmore et al, 2003) pregnenolone 16a-carbonitrile (PCN) Pregnane X receptor (PXR) agonist or antiglucocorticoid (Cai et al, 2002) Rifampicin Bactericidal antibiotics (Donato et al, 2000) Trans-4,5-dihydroxy-1,2-dithiane (DTTox) Intramolecular disulfide form of dithiothreitol; reducing agent (Gilmore and Kirby, 2004) (Montero et al, 1999) Bilirubin Bilirubin (BR) is the end product of heme catabolism, and heme is found in hemoglobin or other hemoproteins such as cytochromes, catalase, and a small pool of unbound free heme (Roy-Chowdhury et al, 2007). BR consists of a tetrapyrrole ( Figure D1).…”

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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“…CYP2E1 contributes to ethanol-induced oxidative stress and EFL in mice associating with increased generation of ROS (Lu et al, 2010;Gilmore et al, 2003). In our study, PD treatment decreased the levels of oxidative stress by decrease the levels of MDA, CYP2E1 and ROS in rats.…”

Section: Discussionmentioning

confidence: 56%

Improving Effect of Platycodin D on Ethanol-Induced Fatty Liver via Keap1-Nrf2-Are Signal Path

Wu¹,

Zhou²,

Yang³

et al. 2017

AJTCAM

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Background: Platycodin D (PD) is one of the important active ingredients in the root of the Platycodon grandiflorum (Jacq.) A. DC (PG), a traditional medicine with many pharmacological activities, especially hepatoprotective activity. There are some researches on the mechanism of liver protection, but it is not very clear. It is necessary to investigate it deeply. Materials and Methods: In order to evaluate the effect of PD on ethanol-induced fatty liver (EFL) and investigate the possible mechanism, the EFL models of rats and BRL-3A cells were set up and treated with PD of 20, 30 mg/kg body weight/day for four weeks, respectively. The hepatic histochemistry, liver function enzymes, oxidative stress levels, antioxidant enzymes and signal path enzymes were assayed. Results: PD significantly (P<0.01) activates signal path enzymes of Keap1, Nrf2 and small Maf either in vitro or in vivo, increases hepatic antioxidant enzyme expression of HO-1, SOD and GSH-Px, improves the oxidative stress indicated by CYP2E1, ROS, T-AOC capacity and MDA contents, reduces levels of serum ALT and AST, and then improves the liver injury degree by histological evaluation. Conclusion: PD is an effective inhibitor of EFL to ameliorate liver impairment ethanol-induced via Keap1-Nrf2-ARE signal path.

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Effects of lipopolysaccharide-stimulated inflammation and pyrazole-mediated hepatocellular injury on mouse hepatic Cyp2a5 expression

Cited by 39 publications

References 50 publications

Hepatic Cytochrome P450 Enzyme Alterations in Humans with Progressive Stages of Nonalcoholic Fatty Liver Disease

Hepatic Cytochrome P450 Enzyme Alterations in Humans with Progressive Stages of Nonalcoholic Fatty Liver Disease

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

Improving Effect of Platycodin D on Ethanol-Induced Fatty Liver via Keap1-Nrf2-Are Signal Path

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