Mammalian class theta GST and differential susceptibility to carcinogens: a review

Glutathione S-transferases (GSTs) are an important part of the cellular det oxification system and, perhaps, evolved to protect cells against reactive oxygen metabolites. Theta is considered the most ancient among the GSTs and theta-like GSTs are found in mammals, fish, insects, plants, unicellular a lgae, and bacteria. It is thought that an ancestral theta-gene underwent an early duplication before the divergence of fungi and animals and further d uplications generated the variety of the other classes of GSTs (alpha, mu, phi, etc.). The comparison of the aminoacidic homologies among mammals sugg ests that a duplication of an ancient GST theta occurred before the speciat ion of mammals and resulted in the subunits GSTT1 and GSTT2. The ancestral GST theta has a dehalogenase activity towards several halogenated compounds , such as the dichloromethane. In fact, some aerobic and anaerobic methylot rophic bacteria can use these molecules as the sole carbon and energy sourc e. The mammalian GST theta cannot sustain the growth of bacteria but still retains the dehalogenating activity. Therefore, although mammalian GST thet a behaves as a scavenger towards electrophiles, such as epoxides, it acts a lso as metabolic activator for halogenated compounds, producing a variety o f intermediates potentially dangerous for DNA and cells. For example, mice exposed to dichloromethane show a dose-dependent incidence of cancer via th e GSTT1-1 pathway. Because GSTT1-1 is polymorphic in humans, with about 20% of Caucasians and 80% of Asians lacking the enzyme, the relationship betwe en the phenotype and the incidence of cancer has been investigated extensiv ely in order to detect GSTT1-1-associated differential susceptibility towar ds endogenous or exogenous carcinogens. The lack of the enzyme is related t o a slightly increased risk of cancer of the bladder, gastro-intestinal tra ct, and for tobacco-related tumors (lung or oral cavity). More pronounced r isks were found in males with the GSTT1-null genotype for brain diseases an d skin basal cell carcinomas not related to sunlight exposures. Moreover, t here was an increased risk of kidney and liver tumors in humans with the GS TT1-1 positive genotype following exposures to halogenated solvents. Intere stingly, the liver and kidney are two organs that express the highest level of GST theta in the human body. Thus, the GSTT1-1 genotype is suspected to confer decreased or increased risk of cancer in relation to the source of exposure; in vitro studies, mostly conducted on metabolites of butadiene, c onfirm the protective action of GSTT1-1, whereas, thus far, experimental st udies prove that the increasing risk is limited. (C) 2000 Elsevier Science B.V. All rights reserved.