S. Dhakshinamoorthy⁽¹⁾, D. Bloom⁽²⁾, Anil Jaiswal^(3)
(1)(2)Department of Pharmacology. Baylor College of Medicine. - Houston. United States
⁽³⁾Baylor College of Medicine - Houston. United States

Induction of Genes Encoding Enzymes that Detoxify Xenobiotics and Carcinogens.

The expression and induction of enzymes that metabolize xenobiotics, drugs and carcinogens play an important role in determining the risk of cancer in human ^(13-21). In other words, the development of chemically induced neoplasia is regulated by a balance between phase I (cytochromes P450, cytochrome P450 reductase, hydroxylases, lipoxygenases, peroxidases and oxidases), which activate carcinogens, and phase II (detoxifying/chemopreventive) enzymes, which detoxify them. The phase II (detoxifying) enzymes include NAD(P)H:Quinone Oxidoreductases (NQOs), which catalyze obligatory two-electron reduction of quinones and their derivatives thus preventing their participation in redox cycling and oxidative stress ^(13-17); glutathione S-transferases (GSTs), which conjugate hydrophobic electrophiles and reactive oxygen species with glutathione (GSH) ^(18-21); UDP-glucuronosyl transferases (UDP-GT), which catalyze the conjugation of glucuronic acid with xenobiotics and drugs for their excretion ⁽²²⁾; epoxide hydrolase (EH), which inactivates epoxides ⁽²³⁾; g-glutamylcysteine synthetase (g-GCS), which plays a key role in the regulation of glutathione metabolism ⁽⁶⁾ and so on.

Among the various detoxifying enzymes, the NQOs and the GSTs have been extensively studied. The NQO gene family contains two members designated as NQO1 and NQO2 ^(15-17). Mutations in the NQO1 gene resulting in the loss of NQO1 enzyme activity have been reported in certain types of cancers ^(24-30). Various GSTs including the GST Ya and GST P genes are encoded by five gene families ⁽²⁰⁾. Loss of GSTs are associated with several kinds of cancer. This includes prostate, urothelial, lung and colorectal cancer ^(31-34).

In addition to the detoxification enzymes, several other enzymes also protect cells from oxidative stress by preventing the generation of superoxide or by scavenging superoxide. These enzymes include heme oxygenase-1 (HO-1), superoxide dismutase-1 (SOD-1; also referred to as Cu/Zn SOD) and catalase ^(35-37). HO-1 increases the intracellular levels of ferritin ⁽³⁵⁾. The increase in ferritin limits the availability of iron to catalyze harmful reactions, such as the peroxidation of lipids and the fenton reaction producing hydroxyl radicals thus, protecting the cells against UV induced oxidative stress.

Studies have revealed that the capacity of many diverse chemicals to block carcinogenesis correlates with their capacity to induce NQO1 and other detoxifying enzymes including GSTs ⁽¹³⁾. Induction of NQO1 and GST by Sulforaphane from Saga broccoli blocks the formation of mammary tumors in Sprague-Dawley rats treated with single dose of 9,10 dimethyl-1,2-benzanthracene ⁽³⁸⁾.

The Genes encoding the human and rat NQO1, human NQO2, rat GST Ya and rat GST P were cloned and sequenced ^(39-44). Among these genes, the regulation of NQO1 and GST Ya expression is best studied. The NQO1 and GST Ya genes are expressed at higher levels in liver tumors and tumor cells as compared to normal liver and liver hepatocytes. These genes are coordinately induced in response to xenobiotics and antioxidants ^(17,20,45).

Discussion Board

Any Comment to this presentation?

[ABSTRACT] [Antioxidants and their Mode of Action] [Induction of Genes Encoding Enzymes that Detoxify Xenobiotics and Carcinogens.] [Antioxidant Response Element] [Figures] [Figures-2] [Antioxidant Response Element-Binding Proteins] [Summary and Conclusions] [Acknowledgements] [References] [Discussion Board]

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S. Dhakshinamoorthy, D. Bloom, Anil Jaiswal
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Last update: 24/01/00