Stabilization of Cytochrome P450j Messenger Ribonucleic Acid in the Diabetic Rat

Song, Byeong Jun; Matsunaga, Tamihide; Hardwick, James P.; Park, Sang S.; Veech, Richard L.; Yang, Chung S.; Gelboin, Harry V.; Gonzalez, Frank J.

doi:10.1210/mend-1-8-542

Cited by 190 publications

(72 citation statements)

References 33 publications

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“…Additional pro-oxidants in fatty livers might be produced via the cytochrome P 450 system. Increased hepatic cytochrome P450 II E has been reported in diabetes 31 and on diets that induce either choline deficiency 32 or obesity, 33 conditions associated with increased concentrations of fatty acids in the liver similar to obese Zucker rats.…”

Section: Discussionmentioning

confidence: 99%

Oxidative stress in fatty livers of obese Zucker rats: Rapid amelioration and improved tolerance to warm ischemia with tocopherol

2001

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Fatty livers in humans and rats are less tolerant of ischemia, endotoxin, and alcohol. We hypothesized that fatty livers of obese (Ob) Zucker rats are oxidatively stressed and oxidative stress could be relieved by antioxidant treatment, leading to improved tolerance to ischemia. Total glutathione (GSH), tocopherol (TOC), ascorbic acid (AA), catalase (CAT), superoxide dismutase (SOD), and selenium-glutathione peroxidase (Se-GPx) were measured in the livers of Ob and lean (Ln) Zucker rats before and after treatment with high-dose TOC and ascorbate. Also, survival in treated Ob rats following a lethal 90 minutes of partial in vivo warm ischemia was examined. Fatty livers of Ob rats contained significantly less GSH, TOC, and CAT, in comparison with livers of Ln rats. Immunoblotting showed significantly decreased CAT protein without changes in mRNA in fatty livers. There were no significant differences in AA, SOD, and Se-GPx between the 2 groups. Pretreatment with TOC and ascorbate over 48 hours completely corrected the decreases in GSH, TOC, and CAT. Most importantly, TOC with or without ascorbate pretreatment significantly improved survival in Ob rats following ischemia in a dosedependent manner. Fatty livers in humans and experimental animals are more prone to a variety of insults such as ischemia/reperfusion (I/ RP), endotoxin, and alcohol. Nonalcoholic steatohepatitis and its progression to cirrhosis are well-defined clinical entities. 1 Recipients of human donor livers with moderate or severe steatosis have decreased graft and patient survival. 2 Although exact figures are not available, it is believed that as many as 30% of donor livers have varying degrees of steatosis on routine microscopic examination. About 10% of donor livers are not used for transplantation because of moderate to severe steatosis, and this worsens the current shortage of livers. 2 Treatment regimens that will improve tolerance of fatty livers to the aforementioned insults are needed, and would benefit a diverse group of patients.Two rodent models of fatty liver, the genetically obese (Ob) and lipotrope-deficient diet models, are used in the laboratory to further investigate the problems associated with fatty livers. Abnormalities in sinusoidal microcirculation, 3,4 mitochondrial oxidative phosphorylation including a decrease in adenosine triphosphate production, 5,6 and dysregulation of cytokine production 7 are some of the mechanisms that have been associated with the increased injury to fatty livers in both rodents and humans. Oxidative stress has recently been postulated to be a common feature in fatty livers of diverse etiologies. 1 Lipid peroxidation products in the liver are increased in both models of rat fatty liver. 8,9 Reactive oxygen intermediates are key mediators of I/RP injury in solid organs. Thus, a 2-step oxidative injury comprised of a chronic oxidative stress before and an additional acute oxidative stress following I/RP may explain the increased injury sustained by fatty livers following both cold and warm ischemia.To...

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Section: Discussionmentioning

confidence: 99%

Oxidative stress in fatty livers of obese Zucker rats: Rapid amelioration and improved tolerance to warm ischemia with tocopherol

2001

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“…Earlier studies have reported that the induction of CYP2E1 seems to be regulated at the post-transcriptional or post-translational levels by the stabilization of mRNA [4] or protection against the rapid degradation of protein [5,19]. To obtain a clue towards understanding the mechanisms, we investigated the possibility that miRNAs may be involved in the regulation of human CYP2E1.…”

Section: Discussionmentioning

confidence: 99%

“…It should be noted that the induction of CYP2E1 protein by these chemicals was not necessarily accompanied by an increase of CYP2E1 mRNA level [3]. The proposed mechanisms for the induction of CYP2E1 are the stabilization of mRNA [4] or protein [5]. Previously, Sumida et al [6] reported that the CYP2E1 mRNA levels in 15 human liver samples were not positively correlated with the chlorzoxazone 6-hydroxylase activities, which is a probe activity of CYP2E1.…”

Section: Introductionmentioning

confidence: 99%

Human CYP2E1 is regulated by miR-378

Mohri

Nakajima

Fukami

et al. 2010

Biochemical Pharmacology

152

101

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Human CYP2E1 is one of the pharmacologically and toxicologically important cytochrome P450 isoforms. Earlier studies have reported that the CYP2E1 expression is extensively regulated by post-transcriptional and post-translational mechanisms, but the molecular basis remains unclear. In the present study, we examined the possibility that microRNA may be involved in the post-transcriptional regulation of human CYP2E1. In silico analysis identified a potential recognition element of miR-378 (MRE378) in the 3'-untranslated region (UTR) of human CYP2E1 mRNA. Luciferase assays using HEK293 cells revealed that the reporter activity of the plasmid containing the MRE378 was decreased by co-transfection of precursor miR-378, indicating that miR-378 functionally recognized the MRE378. We established two HEK293 cell lines stably expressing human CYP2E1 including or excluding 3'-UTR. When the precursor miR-378 was transfected into the cells expressing human CYP2E1 including 3'-UTR, the CYP2E1 protein level and chlorzoxazone 6-hydroxylase activity were significantly decreased, but were not in the cells expressing CYP2E1 excluding 3'-UTR. In both cell lines, the CYP2E1 mRNA levels were decreased by overexpression of miR-378, but miR-378 did not affect the stability of CYP2E1 mRNA. In a panel of 25 human livers, no positive correlation was observed between the CYP2E1 protein and CYP2E1 mRNA levels, supporting the post-transcriptional regulation. Interestingly, the miR-378 levels were inversely correlated with the CYP2E1 protein levels and the translational efficiency of CYP2E1. In conclusion, we found that human CYP2E1 expression is regulated by miR-378, mainly via translational repression. This study could provide new insight into the unsolved mechanism of the post-transcriptional regulation of CYP2E1.

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“…The regulation of CYP2E1 is considered to involve multiple mechanisms including transcriptional activation (Ueno and Gonzalez, 1990), stabilization of mRNA (Song et al, 1987), posttranslational modifications (Song et al, 1989), and substrate stabilization of the protein against degradation (Eliasson et al, 1988). The induction of hepatic CYP2E1 proteins by ethanol can occur at transcriptional and/or post-transcriptional levels; ligandmediated protein stabilization is thought to be the primary mechanism at relatively low ethanol doses (Eliasson et al, 1988).…”

Section: Discussionmentioning

confidence: 99%

Differential induction of ethanol-metabolizing CYP2E1 and nicotine-metabolizing CYP2B1/2 in rat liver by chronic nicotine treatment and voluntary ethanol intake

Yue

Khokhar

Miksys

et al. 2009

European Journal of Pharmacology

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Alcohol and nicotine are frequently co-used and co-abused, and use of both drugs alone can affect hepatic drug metabolism. We investigated the influences of chronic nicotine treatment and voluntary ethanol intake on the induction of rat hepatic cytochrome P450 (CYP) enzymes that metabolize ethanol and nicotine. Rats were trained to voluntarily drink ethanol (6% v/v, 1 h) with nicotine pretreatment for 10 days. Another group of rats were treated with the same nicotine doses alone. Hepatic CYP2E1, CYP2B1/2 and CYP2D1 proteins were assessed by immunoblotting. Nicotine pretreatment (0.4, 0.8 and 1.2 mg/kg) increased voluntary ethanol intake on day 10 by 1.8, 2.0, and 1.4 fold respectively compared to saline pretreatment (P<0.01-0.3). CYP2E1 was increased 1.7, 1.8, and 1.4 fold by the three doses of nicotine alone (P<0.02-0.21); CYP2E1 levels were increased by voluntary ethanol intake alone and a further 2.4, 2.2, and 1.8 fold by 0.4, 0.8, and 1.2 mg/kg nicotine respectively versus saline pretreatment (P<0.002-0.06). CYP2B1/2 proteins were not induced by nicotine alone, but were increased by 2.2-2.5 fold by ethanol drinking (P<0.05). CYP2E1 (r=0.67, P<0.001) and CYP2B1/2 levels (r=0.49, P=0.007) correlated with alcohol consumption on day 10. There was no change in CYP2D1. Chronic nicotine increased voluntary ethanol intake thereby enhancing CYP2E1 and CYP2B1/2 levels. Thus CYPs are regulated not only directly by nicotine and ethanol, but also indirectly via an increase in the ethanol consumption in the presence of nicotine pretreatment. Together this may contribute to the co-abuse of these drugs and alter the metabolism of clinical drugs and endogenous substrates.

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Stabilization of Cytochrome P450j Messenger Ribonucleic Acid in the Diabetic Rat

Cited by 190 publications

References 33 publications

Oxidative stress in fatty livers of obese Zucker rats: Rapid amelioration and improved tolerance to warm ischemia with tocopherol

Oxidative stress in fatty livers of obese Zucker rats: Rapid amelioration and improved tolerance to warm ischemia with tocopherol

Human CYP2E1 is regulated by miR-378

Differential induction of ethanol-metabolizing CYP2E1 and nicotine-metabolizing CYP2B1/2 in rat liver by chronic nicotine treatment and voluntary ethanol intake

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