Elsevier

Toxicology

Volume 132, Issues 2–3, 15 February 1999, Pages 85-98
Toxicology

Review
Metallothionein in radiation exposure: its induction and protective role

https://doi.org/10.1016/S0300-483X(98)00150-4Get rights and content

Abstract

Since its discovery about 40 years ago, there has been a wide interdisciplinary research interest in metallothionein (MT) on its physiological and toxicological aspects. Functionally, MT is involved not only in metal detoxification and homeostasis, but also in scavenging free radicals during oxidative damage. Among over 4500 publications which can be retrieved by Medline search, only about 50 reports have been published on the relationship of MT with ionizing and UV radiation. In this review, we have evaluated critically the published data on the induced synthesis of MT by radiation, and the potential functions of MT in radiation induced cell damage. MT mRNA expression or MT synthesis was found to be induced by exposure of cells in vitro or tissues in vivo to ionizing or UV radiation. In most of the studies in animals and tissue cultures, high doses of ionizing radiation were used to induce MT, and, therefore, it is difficult to extrapolate these results to low level of repeated exposures to radiation in humans. Induced synthesis of MT is considered as one of the mechanisms involved in the adaptive response to low dose radiation exposure. The presence of MT in normal cells may provide protective effects from radiation-induced genotoxicity and cytotoxicity. However, in tumor cells, the presence of MT can result in drug and radiation resistance as well. These effects are modulated by other cellular factors, besides MT, such as antioxidants, and by the cell cycle stages in cell proliferation and differentiation.

Introduction

Metallothioneins (MT) are a family of low-molecular weight (about 6–7 kDa), cysteine-rich (30%) intracellular proteins with high affinity for both essential (zinc, Zn and copper, Cu) and non-essential (cadmium, Cd and mercury, Hg) metals. It has been 40 years since MT, a Cd- and Zn-binding protein, was isolated first from horse kidney (Margoshes and Vallee, 1957). During the last four decades, there have been several reports on the function and structure of MT, but the number of publications on MT and radiation exposure is few. However, radiation is used widely for cancer treatment and the role of MT induction in radiation exposure is of great interest. In this review article, we have tried to evaluate critically the published data on MT and radiation.

There are four isoforms of MT: MT-I, -II, -III and -IV in the mammalian organs. Among them, MT-I and -II are the most predominant isoforms and have been well-documented. The two major isoforms of MT, MT-I and -II, contain two distinct adamantine-like metal–thiolate clusters, one with four and another with three metal ions. The isoforms, MT-I and -II are expressed ubiquitously in most mammalian organs, and regulated co-ordinately, whereas the MT-III and -IV isoforms are expressed specifically in the brain and in squamous epithelia, respectively (Chan and Cherian, 1993, Cherian and Chan, 1993, Sato and Bremner, 1993). MT-I and -II mRNA and protein are inducible not only by metals, but also by many non-metallic compounds including ethanol, alkylating agents, and physical or chemical oxidative stress conditions (Cherian and Chan, 1993, Sato and Bremner, 1993). In addition to its principal role in detoxification of potentially toxic heavy metals, and in regulation of the homeostasis of essential trace metals, MT can also act as an antioxidant and a free radical scavenger (Cherian and Chan, 1993, Sato and Bremner, 1993, Cherian and Ferguson, 1997). The antioxidant or free radical scavenging activity of MT has been compared with reduced glutathione (Thornalley and Vasak, 1985, Miura et al., 1997). The targeted disruption of MT-I and -II genes in MT-null mice made them more sensitive to Cd and anticancer drug cytotoxicity (Masters et al., 1994, Kondo et al., 1995). Therefore, induction of MT synthesis may be one of the important defense mechanisms against Cd toxicity and oxidative damage (Koropatnick and Cherian, 1988). The cellular damage of radiation is mainly an oxidative damage due to the formation of several types of oxygen free radicals including hydroxyl and superoxide radicals by radiolysis of water in cells. Several reports have shown both induced synthesis of MT and a protective role for MT against free radicals during radiation exposure. Since UV radiation-mediated cell injury may also be involved in oxygen radical generation (Black, 1987, Hanada et al., 1992) we describe both ionizing radiation and UV radiation in this review.

Radiotherapy is widely used in the treatment of various types of cancer, and recent reports suggest that the sensitivity of tumors to radiation may depend on their MT levels (Cherian and Chan, 1993, Kondo et al., 1995, Cherian and Ferguson, 1997). Therefore, we have reviewed also the potential role of MT in treatment of cancer with radiation.

Section snippets

Ionizing radiation

The induced synthesis of MT in different organs after whole body irradiation has been reported in rats (Shiraishi et al., 1983, Shiraishi et al., 1986, Togami, 1987, Hayashi, 1988, Shiraishi et al., 1989) and in mice (Matsubara et al., 1986, Matsubara et al., 1987a, Matsubara et al., 1987b, Koropatnick et al., 1989). In certain studies, both MT protein and mRNA contents were found to be induced in a dose-dependent manner in mice (Koropatnick et al., 1989). All these reports are summarized in

Protective role of MT from radiation-induced injury

The rationale for a protective role of MT in the lethal effects of ionizing radiation and UV-radiation was developed based on the following observations: (a) sulfhydryl agents, such as cysteine, cysteamine and glutathione, can protect mammalian cells from radiation-induced DNA damage and cell death, and MT with a high cysteine content (approximately 30%) can also provide similar protection (Cai et al., 1996); (b) ionizing radiation causes about 10% of the DNA damage due to direct energy

Possible role of MT in low-dose radiation-induced adaptive response

Pre-exposure of human lymphocytes or mammalian tissues (Cai and Jiang, 1995, Cai and Wang, 1995) to low-dose ionizing radiation (LDR) can render these cells or tissues more resistant to DNA or chromosomal damage by a subsequent high-dose radiation (HDR), and this resistance is known as an adaptive response. These cells also become cross-resistant to chemical mutagens (bleomycin, mitomycin C (MMC) and cisplatin) (Cai and Jiang, 1995, Cai and Wang, 1995). In addition, pre-treatment with low

Summary

Most of the published reports on the induction of MT after exposure to ionizing and UV radiation are on rodent experimental models and cells in culture. It is difficult to extrapolate these results directly to human exposure conditions. However, in general, these studies suggest that repeated low doses of exposure are better than a large single radiation exposure to induce MT synthesis. It is unclear whether radiation itself can induce MT synthesis or these effects are secondary due to the

Acknowledgements

Dr M. George Cherian was a visiting scientist at the National Institute for Environmental Studies at Tsukuba and was supported by a Science and Technology Agency (STA) Fellowship.

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