Prostaglandin H Synthases and their Importance in Chemical Toxicity

Author: Vogel C.

Source: Current Drug Metabolism, Volume 1, Number 4, December 2000 , pp. 391-404(14)

Publisher: Bentham Science Publishers

Abstract:

The metabolism of a xenobiotic is an important stage resulting in its toxification (bioactivation) or detoxification. The most common reaction is the oxidation catalyzed by the cytochrome P450 (CYP) enzyme system. An alternate enzyme for chemical oxidation is the prostaglandin H synthase (PGHS) also known as cyclooxygenase (COX). The PGHS is the initial enzyme in arachidonate metabolism and formation of prostanoids such as prostaglandins (PG), prostacyclins, and thromboxanes. However, 25 years ago it was found that during the reduction of the endogenous substrate, hydroperoxy-endoperoxide (PGG2) to hydroxy-endoperoxide (PGH2), the PGHS enzyme is capable to co-oxidize chemicals. In this reaction, a broad spectrum of chemicals can serve as electron donors such as phenolic compounds, aromatic amines, and polycyclic aromatic hydrocarbons. In contrast to numerous CYP enzymes in liver, the PGHS is an alternate enzyme for xenobiotic metabolism in extrahepatic tissues. In respect of tissue distribution, PGHS can play an essential role in the bioactivation of e.g. procarcinogenic chemicals in certain target tissues that possess low CYP monooxygenase activity.

Two PGHS isozymes have been identified PGHS-1 and PGHS-2, which have very similar kinetic properties, but differ in regard to expression and regulation. In recent studies it was shown that not only endogenous stimuli but also drugs and environmental chemicals can activate PGHS-2 expression. Therefore the PGHS enzymes provide two interesting aspects for pharmacology and toxicology a) the co-oxidation of chemicals and b) the altered synthesis of prostanoids after exposure to certain xenobiotics which can be essential for their ultimate toxicity.

Keywords: Prostaglandin H synthases; chemical toxicity; xenobiotics; PGHS enzyme; prostanoids; pharmacogenetics

Language: English

Document Type: Review article

DOI: http://dx.doi.org/10.2174/1389200003338884

Publication date: 2000-12-01

• Current Drug Metabolism aims to cover all the latest and outstanding developments in drug metabolism and disposition. The journal serves as an international forum for the publication of timely reviews in drug metabolism. Current Drug Metabolism is an essential journal for academic, clinical, government and pharmaceutical scientists who wish to be kept informed and up-to-date with the latest and most important developments. The journal covers the following areas:
  
  In vitro systems including CYP-450; enzyme induction and inhibition; drug-drug interactions and enzyme kinetics; pharmacokinetics, toxicokinetics, species scaling and extrapolations; P-glycoprotein and transport carriers; target organ toxicity and interindividual variability; drug metabolism and disposition studies; extrahepatic metabolism; phase I and phase II metabolism; recent developments for the identification of drug metabolites and adducts.

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• In this Subject: Anatomy & Physiology ,  Pharmacology
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