Role of cytochromes P450 in chemical toxicity and oxidative stress: studies with CYP2E1

Bai

Molecular Medicine Reports

et al. 2014

Abstract. Schisandra chinensis is a well-known traditional medicinal herb. Acetaminophen is a commonly used over-the-counter analgesic and overdose of acetaminophen was the most frequent cause of acute liver failure. However, no studies have demonstrated the role of Schisandra chinensis in acetaminophen-induced acute liver failure to the best of our knowledge. In this study, an acute liver injury model was established in mice using acetaminophen. The protective role of Schisandra chinensis was detected by histopathological analysis, and measurement of the serum transaminase levels and hepatic Cyp activity levels in the mouse model. Subsequently, hepatocytes were isolated from the livers of the mouse model. The cell cycle, apoptosis, mitochondrial membrane potential and reactive oxygen species were determined using flow cytometry. Cell proliferation and 26S proteasome activity were determined using spectrophotometry. Schisandra chinensis was found to resist acetaminophen-induced hepatotoxicity by protecting mitochondria and lysosomes and inhibiting the phosphor-c-Jun N-terminal kinase signaling pathway. These findings provide a novel application of Schisandra chinensis against acetaminophen-induced acute liver failure.

Section: Discussionsupporting

confidence: 45%

Inhibitory effects of Schisandra chinensis on acetaminophen-induced hepatotoxicity

Bai

Molecular Medicine Reports

et al. 2014

Free Radical Biology and Medicine

“…CYP2E1 knockout mice were developed by Gonzalez and colleagues to determine the role of CYP2E1 in xenobiotic metabolism and toxicity (49,177,178). The development of the CYP2E1 knockout mouse has been of great value in establishing the role of CYP2E1 in the metabolism and toxicity of various hepatotoxins.…”

Section: The Cyp2e1 Knockout Mousementioning

confidence: 99%

CYP2E1 and oxidative liver injury by alcohol

Cederbaum

2008

651

534

Ethanol-induced oxidative stress appears 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 appears 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 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 to understand the actions of CYP2E1 and its role in alcoholic liver injury.

“…These are plasma membrane NADPH oxidases that are highly expressed in astrocytes and oligodendrocytes (44,45), cytochromes P450 (46), and even catecholamine derivatives (47). Thus, elevated rates of basal ROS production by catecholamine metabolism might explain the high loads of mtDNA deletions observed in aged substatia nigra neurons (48,49).…”

Section: Mitochondrial Formation Of Ros and Neurodegenerationmentioning

confidence: 99%

Mitochondrial involvement in neurodegenerative diseases

Kunz

2013

IUBMB Life

The classical bioenergetical view of the involvement of mitochondria in neurogeneration is based on the fact that mitochondria are the central players of ATP synthesis in neurons and their failure leads to neuronal dysfunction and eventually to cell death. Mutations in at least 39 genes in inherited neurodegenerative disorders seem to alter directly or indirectly mitochondrial function. Most of these mutations do not directly affect oxidative phosphorylation, but act through disturbed mitochondrial dynamics and quality control. This, however, does not invalidate the bioenergetic hypothesis.Neurodegeneration is not necessarily associated with a gross failure of ATP production, but might rather be a consequence of local insufficiencies of ATP supply in critical compartments of neurons, like the presynaptic terminal. We hypothesize that slow disease progression, at least in a subgroup of neurodegenerative diseases, can be explained by the parallel action of subcellular ATP insufficiency and clonal expansion of somatic mitochondrial DNA mutations, and particularly deletions. V C 2013 IUBMB Life, 65(3): [263][264][265][266][267][268][269][270][271][272] 2013