Cytochromes P450 in the Bioactivation of Chemicals

Ioannides, Costas; Lewis, David F.

doi:10.2174/1568026043387188

Cited by 195 publications

(128 citation statements)

References 159 publications

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“…It is impossible to distinguish whether the increase in these activities is caused by the glucosinolate itself or due to sulforaphane released from the action of intestinal microflora (Getahun and Chung, 1999). In order to answer this query, studies using human hepatoma HepG2 cell lines were conducted to evaluate the capability of glucoraphanin and its breakdown product sulforaphane in modulating cytochrome P450 enzymes of the CYP1 family, the most vital phase I enzymes involved in xenobiotic metabolism (Ioannides and Lewis, 2004), and also phase II detoxifying enzymes such as quinone reductase and glutathione S-transferase.…”

Section: Discussionmentioning

confidence: 99%

Sulforaphane is Superior to Glucoraphanin in Modulating Carcinogen-Metabolising Enzymes in Hep G2 Cells

Razis

Noor²

2013

Asian Pacific Journal of Cancer Prevention

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Glucoraphanin is the main glucosinolate found in broccoli and other cruciferous vegetables (Brassicaceae). The objective of the study was to evaluate whether glucoraphanin and its breakdown product sulforaphane, are potent modulators of various phase I and phase II enzymes involved in carcinogen-metabolising enzyme systems in vitro. The glucosinolate glucoraphanin was isolated from cruciferous vegetables and exposed to human hepatoma cell line HepG2 at various concentrations (0-25 µM) for 24 hours. Glucoraphanin at higher concentration (25 µM) decreased dealkylation of methoxyresorufin, a marker for cytochrome P4501 activity; supplementation of the incubation medium with myrosinase (0.018 U), the enzyme that converts glucosinolate to its corresponding isothiocyanate, showed minimal induction in this enzyme activity at concentration 10 µM. Quinone reductase and glutathione S-transferase activities were unaffected by this glucosinolate; however, supplementation of the incubation medium with myrosinase elevated quinone reductase activity. It may be inferred that the breakdown product of glucoraphanin, in this case sulforaphane, is superior than its precursor in modulating carcinogenmetabolising enzyme systems in vitro and this is likely to impact on the chemopreventive activity linked to cruciferous vegetable consumption.

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Section: Discussionmentioning

confidence: 99%

Sulforaphane is Superior to Glucoraphanin in Modulating Carcinogen-Metabolising Enzymes in Hep G2 Cells

Razis

Noor²

2013

Asian Pacific Journal of Cancer Prevention

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“…These carcinogens are indirect-acting so that in order to elicit their carcinogenicity they must first be metabolically converted to DNA-binding species, and this process is largely catalysed by cytochromes P450 [27]. Such bioactivation can take place in situ, but there is also experimental evidence to support the view that reactive intermediates generated in the liver, the principal site of bioactivation, may be transported to extrahepatic tissues although the underlying mechanism(s) remain elusive [28,29].…”

Section: Discussionmentioning

confidence: 99%

Modulation of rat pulmonary carcinogen-metabolising enzyme systems by the isothiocyanates erucin and sulforaphane

Hanlon

Coldham

Sauer

et al. 2009

Chemico-Biological Interactions

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“…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).…”

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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Cytochromes P450 in the Bioactivation of Chemicals

Cited by 195 publications

References 159 publications

Sulforaphane is Superior to Glucoraphanin in Modulating Carcinogen-Metabolising Enzymes in Hep G2 Cells

Sulforaphane is Superior to Glucoraphanin in Modulating Carcinogen-Metabolising Enzymes in Hep G2 Cells

Modulation of rat pulmonary carcinogen-metabolising enzyme systems by the isothiocyanates erucin and sulforaphane

Structures of Human Cytochrome P-450 2E1

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