Development of Oxidative Stress by Cytochrome P450 Induction in Rodents Is Selective for Barbiturates and Related to Loss of Pyridine Nucleotide-dependent Protective Systems

Dostálek, Miroslav; Hardy, Klarissa D.; Milne, Ginger L.; Morrow, Jason D.; Chen, Chi; Gonzalez, Frank J.; Gu, Jun; Ding, Xinxin; Johnson, Dale G.; Johnson, Jeffrey A.; Martin, Martha V.; Guengerich, F. Peter

doi:10.1074/jbc.m802447200

Cited by 77 publications

(45 citation statements)

References 70 publications

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“…Enzymatic processses resulting in the metabolization of xenobiotics with the involvement of cytochrome P450 may also have contributed to an increase in reactive oxygen species following the administration of the analysed compounds (Dostalek et al 2008). Limited data in the literature suggests the possibility of modifying the system of cytochrome P450 by both pesticides and drugs (Bapiro et al 2001, Jokanovic 2001.…”

Section: Discussionmentioning

confidence: 99%

Glutathione and glutathione-related enzymes in rats exposed to dimethoate and/or pyrantel

Spodniewska¹,

Barski²,

Ziółkowski³

2014

Polish Journal of Veterinary Sciences

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The study was undertaken to examine the effect of single and combined administration of dimethoate (an OP insecticide) and pyrantel embonate (an anthelmintic agent) on the concentration of reduced glutathione (GSH) and the activity of glutathione peroxidase (GPx) and glutathione reductase (GR) in rats. Dimethoate (Group I) was administered to rats at a dose of 1/10 LD 50 for 5 consecutive days and pyrantel embonate (Group II) at a dose of 1/5 LD 50 for 3 consecutive days. The animals of group III were given both of the mentioned above compounds in the same manner as group I and II, but pyrantel embonate was applied on day 3, 4, and 5 from the beginning of dimethoate intoxication. Material from 6 rats randomly selected from each group was obtained after 3, 6 and 12 hours and 2, 7 and 14 days following the last applied dose of the compounds under study. It was found that application of pyrantel embonate caused only slight changes in the analysed parameters i.e. GSH, GPx and GR. Dimethoate administration caused disturbances in the antioxidative system manifested as a decrease in GSH concentration in the liver (max. -37.7% after 6 hours) and an increase of GPx and GR activities in erythrocytes (max. -21.7% and 29.6% after 3 hours, respectively), compared to the control group. The profile of changes after combined intoxication was similar, but their intensity was higher compared to the group of animals exposed to dimethoate only. Based on current studies, it was concluded that both dimethoate and pyrantel embonate at the applied doses showed a pro-oxidative activity.

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Section: Discussionmentioning

confidence: 99%

Glutathione and glutathione-related enzymes in rats exposed to dimethoate and/or pyrantel

Spodniewska¹,

Barski²,

Ziółkowski³

2014

Polish Journal of Veterinary Sciences

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“…Further, Mito-CP and DAS both restored the GSH level to the untreated control cell level, showing a marked protection against alcohol-induced oxidative stress. Lipid peroxidation is an immediate consequence of oxidative stress (76,77), and the levels of F2-isoprostanes are probably the most reliable measure of oxidative stress (76 -78). Consistent with this result, the cellular isoprostane levels were found to be markedly increased in W23/30R cells following treatment with ethanol (Fig.…”

Section: Electron Transfer Systemmentioning

confidence: 99%

Human Cytochrome P450 2E1 Mutations That Alter Mitochondrial Targeting Efficiency and Susceptibility to Ethanol-induced Toxicity in Cellular Models

Bansal

Anandatheerthavarada

Prabu

et al. 2013

Journal of Biological Chemistry

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Background: Induced expression of CYP2E1 is known to enhance alcohol liver toxicity. Results: Novel mutations W23R/W30R and L32N in human CYP2E1 alter mitochondrial and microsomal targeting efficiency. Conclusion: Human variants with altered targeting modulate susceptibility of cells to alcohol. Significance: Carriers of the novel W23R/W30R mutation in CYP2E1 are likely to be more susceptible to alcohol toxicity.

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“…For example, evidence shows that ethanol consumption substantially increases the levels of CYP2E1 protein, and the resulting ROS have been suggested as the primary contributors to the negative physiological consequences of alcohol-induced liver disease (10). However, studies with induction of CYP2E1 or CYP2E1 knock-out mice have not detected alterations in the in vivo levels of ROS-mediated isoprostanes, a measure of oxidative stress (11).…”

mentioning

confidence: 99%

Structures of Human Cytochrome P-450 2E1

Porubsky¹,

Meneely²,

Scott

2008

Journal of Biological Chemistry

191

102

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Human microsomal cytochrome P-450 2E1 (CYP2E1) monooxygenates >70 low molecular weight xenobiotic compounds, as well as much larger endogenous fatty acid signaling molecules such as arachidonic acid. In the process, CYP2E1 can generate toxic or carcinogenic compounds, as occurs with acetaminophen overdose, nitrosamines in cigarette smoke, and reactive oxygen species from uncoupled catalysis. Thus, the diverse roles that CYP2E1 has in normal physiology, toxicity, and drug metabolism are related to its ability to metabolize diverse classes of ligands, but the structural basis for this was previously unknown. Structures of human CYP2E1 have been solved to 2.2 Å for an indazole complex and 2.6 Å for a 4-methylpyrazole complex. Both inhibitors bind to the heme iron and hydrogen bond to Thr 303 within the active site. Complementing its small molecular weight substrates, the hydrophobic CYP2E1 active site is the smallest yet observed for a human cytochrome P-450. The CYP2E1 active site also has two adjacent voids: one enclosed above the I helix and the other forming a channel to the protein surface. Minor repositioning of the Phe 478 aromatic ring that separates the active site and access channel would allow the carboxylate of fatty acid substrates to interact with conserved 216 QXXNN 220 residues in the access channel while positioning the hydrocarbon terminus in the active site, consistent with experimentally observed -1 hydroxylation of saturated fatty acids. Thus, these structures provide insights into the ability of CYP2E1 to effectively bind and metabolize both small molecule substrates and fatty acids.Cytochrome P-450 (P-450) 3 is a superfamily of enzymes involved in monooxygenation of both endogenous and exogenous substrates. A subset of these enzymes, including cytochrome P-450 2E1 (CYP2E1), are known for their role in the clearance of drugs and other xenobiotics by introducing or unmasking sites for subsequent conjugation and elimination from the body. From a biochemical standpoint these enzymes are fascinating for the diversity of substrates each xenobioticmetabolizing P-450 can metabolize, yet often with exquisite selectivity in the metabolites generated. Unfortunately, in the process some P-450-mediated metabolism can produce toxic or carcinogenic products. Among cytochrome P-450 enzymes, CYP2E1 is particularly notable for this ability and the resulting toxicity (1). This activity is most substantial in the liver because CYP2E1 comprises over 50% of the hepatic cytochrome P-450 mRNA (2) and 7% of the hepatic cytochrome P-450 protein (3). However, CYP2E1 is also expressed at lower levels in a variety of extrahepatic tissues (4), where it is thought to play a role in the metabolism of important endogenous molecules. CYP2E1 levels and the resulting toxicity varies markedly in response to alcohol consumption (5), diabetes (6), obesity (7), and fasting (8). Thus, the action of CYP2E1 can have a significant influence on human health and drug metabolism.CYP2E1 has been connected with liver toxicity through two ...

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Development of Oxidative Stress by Cytochrome P450 Induction in Rodents Is Selective for Barbiturates and Related to Loss of Pyridine Nucleotide-dependent Protective Systems

Cited by 77 publications

References 70 publications

Glutathione and glutathione-related enzymes in rats exposed to dimethoate and/or pyrantel

Glutathione and glutathione-related enzymes in rats exposed to dimethoate and/or pyrantel

Human Cytochrome P450 2E1 Mutations That Alter Mitochondrial Targeting Efficiency and Susceptibility to Ethanol-induced Toxicity in Cellular Models

Structures of Human Cytochrome P-450 2E1

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