Transcriptional control of CYP2E1 in the perivenous liver region and during starvation

doi:10.1016/S0006-291X(05)81061-7

Biochemical and Biophysical Research Communications

Volume 173, Issue 1, 30 November 1990, Pages 331-338

https://doi.org/10.1016/S0006-291X(05)81061-7 Get rights and content

Previous data indicate that the CYP2E1 gene is transcriptionally activated after birth, but that the expression of ethanol-inducible CYP2E1 protein, hereafter, is regulated by post-transcriptional mechanisms. The constitutive expression of CYP2E1 protein is restricted to the perivenous region of the liver lobule. Here we present results from in situ hybridization and run off experiments indicating that this regioselectivity is caused by a higher rate of gene transcription in the perivenous hepatocytes. We also show that transcription of the CYP2E1 gene is activated by starvation, indicating that also this P450 gene is under transcriptional control under certain physiological conditions.

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This was not the case for any of the other analysed CYPs. The CYP2E1 mRNA and protein expression has been shown to increase in response to fasting in adult rats (Qu et al., 1998; Johansson et al., 1990; Yin et al., 1995). Thus, it could be suggested that the foetuses with low birth weight likely are undernourished and thereby have increased CYP2E1 mRNA expression.
The liver hosts a great number of enzymatically driven processes, including detoxification. The super-family of enzymes named cytochrome P450 (CYP) is the major participant in that process. The expression of CYPs is affected by several factors including life-stage (foetal vs. adult). In the present study we investigated the impact of birth-weight (high or low birth weight) and life-stage on constitutive expression of porcine hepatic CYP1A1, CYP1A2, CYP2A19, CYP2B22, CYP2C33, CYP2D25, CYP2E1 and CYP3A29, as well as the transcription factors controlling their expression; aryl hydrocarbon receptor, constitutive androstane receptor, pregnane X receptor, C/EBP and hepatocyte nuclear factors 1 and 4. Both RT-PCR and western blotting showed a marked increase in the expression of the adult pigs compared with prenatal pigs. Moreover, CYP2E1 mRNA expression was 7.5 fold higher in foetuses with low birth weight compared with foetuses with high birth weight. Gender did not affect the mRNA expression within the different life-stages. These results indicate a similarity to what is observed in humans and porcine foetuses may therefore be a model for humans when studying expression of CYPs.
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Regulation of CYP2E1 may operate at a variety of levels, from transcriptional activation to posttranslational enzyme stability, depending on the inducing agent or physiological state (Guengerich et al., 1991). To verify whether the induction of CYP2E1 was determined at a transcriptional level, as occurs in conditions of fasting ketosis (Johansson et al., 1990), real time PCR was performed, but no difference was observed between the control and treated group, suggesting that a posttranscriptional or posttranslational mechanism might regulate this isoform. CYP2E1 is a major hepatic CYP enzyme involved in the metabolism of a variety of small molecules, among which we find endogenous substrates such as acetone and fatty acids (Guengerich et al., 1991).
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Xanthohumol, the major prenylated chalcone found in hops, is known to exert several beneficial effects but only few studies evaluated the safety profile of this natural compound with in part discrepant results. Here, we fed female BALB/c mice with a standard diet supplemented with xanthohumol for 3 weeks, and thus, achieved a daily dose of approximately 1000 mg xanthohumol/kg body weight. There were no significant differences in body weight or food intake between mice on standard diet and animals receiving the same diet supplemented with xanthohumol. Histopathological examination of liver, kidney, colon, lung, heart, spleen and thymus revealed no signs of xanthohumol-toxicity, and biochemical serum analysis confirmed normal organ function. Further, xanthohumol treatment did not affect hepatic glycogen content CYP2E1 and CYP1A2 expression levels, but CYP3A11 mRNA was approximately 30% reduced. Expression of several genes indicative of early hepatic inflammation and fibrosis, a hallmark of chronic liver injury, did not differ between xanthohumol treated and control mice. In summary, these results indicate that oral administration of xanthohumol exhibits no adverse effects on major organ function and homoeostasis in mice. Particularly, hepatotoxic effects could be ruled out confirming a good safety profile of xanthohumol as prerequisite for further studies in humans.
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Ethanol-induced oxidative stress seems to play a major role in mechanisms by which ethanol causes liver injury. Many pathways have been suggested to contribute to the ability of ethanol to induce a state of oxidative stress. One central pathway seems to be the induction of cytochrome P450 2E1 (CYP2E1) by ethanol. CYP2E1 metabolizes and activates many toxicological substrates, including ethanol, to more reactive, toxic products. Levels of CYP2E1 are elevated under a variety of physiological and pathophysiological conditions and after acute and chronic alcohol treatment. CYP2E1 is also an effective generator of reactive oxygen species such as the superoxide anion radical and hydrogen peroxide and, in the presence of iron catalysts, produces powerful oxidants such as the hydroxyl radical. This review article summarizes some of the biochemical and toxicological properties of CYP2E1 and briefly describes the use of cell lines developed to constitutively express CYP2E1 and CYP2E1 knockout mice in assessing the actions of CYP2E1. Possible therapeutic implications for treatment of alcoholic liver injury by inhibition of CYP2E1 or CYP2E1-dependent oxidative stress will be discussed, followed by some future directions which may help us to understand the actions of CYP2E1 and its role in alcoholic liver injury.
Single-dose ethanol administration downregulates expression of cytochrome p450 2E1 mRNA in aldehyde dehydrogenase 2 knockout mice
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Citation Excerpt :
Developmental and constitutive regulation also affects the CYP2E1 expression level. For example, starvation increases the gene transcriptional level of CYP2E1 (Johansson et al., 1990) while sex hormones decrease it (Waxman et al., 1989). In contrast to many P450 isozymes, there is little evidence for induction of hepatic CYP2E1 by xenobiotics at the level of gene transcription, instead, xenobiotics appear to stabilize the CYP2E1 message, by increased translation and enzyme stabilization (Ioannides, 1996).
The polymorphism of aldehyde dehydrogenase 2 (ALDH2), denoted ALDH2*2, is very common in East Asian origin. Acetaldehyde, an intermediate metabolite of ethanol, is metabolized very slowly in people with ALDH2*2 because the mutant ALDH2 protein lacks the activity of acetaldehyde metabolism. On the other hand, it is well established that one of the cytochrome P450 enzymes, CYP2E1, is an activator of carcinogens (e.g., nitorosamines) and a generator of oxidative stress, and it is shown that CYP2E1 was induced by ethanol via gene transcriptional regulation. In the present study, to examine the consequences of ALDH2 polymorphism on transcriptional regulation of CYP2E1 in liver tissue, Aldh2+/+ and Aldh2−/− mice were orally administered 5 g/kg body weight of ethanol and the levels of CYP2E1 mRNA in liver tissue then analyzed. The level of CYP2E1 mRNA 12 h after the ethanol administration tended to be higher than the 0-h group in Aldh2+/+ mice, however, it was significantly lower than the 0-h group in Aldh2−/− mice. These findings suggest that single-dose ethanol administration downregulates the expression of cytochrome p450 2E1 mRNA in the presence of inactive ALDH2.

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Transcriptional control of CYP2E1 in the perivenous liver region and during starvation

J. Biol. Chem.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

Biochem. Biophys. Res. Commun.

Meth. Enzymol.