Oxidative Stress Produced by Drugs and Chemicals and the Induction of Heme Oxygenase.

Abstract

Evidence has been accumulating that oxidative stress plays important roles in pathogenesis of various acute and chronic diseases. A wide variety of drugs and chemicals have been shown to produce reactive oxygen species by their oxidative metabolism in the body, thus may cause oxdative stress and lead to cellular and tissue damages. In order to response to such oxidative insults, many antioxidative defense systems are constitutively expressed in mammalian cells the body. Of these antioxidative defense systems, heme oxygenase-1 (HO-1), a first and rate-limiting enzyme of heme degradation, has recently been shown to be highly responsible enzyme against oxidative stress. HO oxidatively cleaves heme into carbon monoxide (CO), Fe2+ and biliverdin, the latter is readily reduced to bilirubin. These degradative byproducts of heme by HO has currently been characterizing their physiological importance. Namely, CO, as just like NO, may play as a gaseous messenger; bilirubin acts as an antioxidant; Fe2+ is a modulator of ferritin. Therefore, the induction of HO-1 produced by physiological and pathophysiological states, and by drugs and chemicals may play vital roles in the adaptive and/or protective response to oxidative stress as a whole. Accumulated evidence demonstrates that HO-1 is induced by not only the substrate heme but also a wide variety of divergent drugs and chemicals, such as hormones, heavy metals, organic compounds including glutathione depletors, cytokines, prostaglandins and so on. Although a detailed mechanism of the induction of HO-1 by these compounds remains to be determined, most of them produce the enzyme induction through oxidative stress. Additionally, it is well established that HO-1 induction in liver or kidney is generally followed by the decrease in cytochrome P-450 content, important enzyme(s) which metabolizes endogenous substances and exogenous drugs and chemicals. This review will describe partly on the current understanding of physiological and/or pathophysiological significance of HO-1, and mainly focus on the significance of this enzyme induction in response to oxidative stress produced by drugs and chemicals. I hope that this review will stimulate interest and understandings in HO-1 and its potential roles in response to oxidative stress.