Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues

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Glutathione S-Transferases (GSTs) [T88.7]

OMIM numbers: 134660 (GSTP1), 138350 (GSTM1), 600436 (GSTT1)

Dipl.-Biol. Birgit Busse

Scientific Background

Glutathione S-transferases (GSTs) are multifunctional enzymes that play a key role in cellular detoxification. There are different GST classes known (GST-A, GST-T, GST-M, GST-P, GST-K, GST-Z). GSTs protect the cell by conjugation of toxic substances with glutathione. Gluthatione conjugates are usually less toxic and exhibit a higher water solubility than the original substances, which facilitates the excretion. However, in the process of detoxification, reactive intermediate metabolites occur that may have a toxic effect. Endogenous substrates of the GSTs are various products of the oxidative metabolism as well as several drugs and xenobiotics such as organic halogenides, alkenes, epoxides and benzpyrenes.

The genes of the GSTs are polymorphic. The deletion alleles of GST-M1 and -T1 as well as the Ile105Val polymorphism of GST-P1 are of high frequency among the population.

GST-T1 exhibits a special affinity to halogens and epoxides such as dichloromethane, bromo-dichloromethane, ethylene dioxide and methyl bromide. Various carcinogens that occur for example in cigarette smoke, are metabolized by GSTs as well. The enzyme catalyzes, among other things, the step-wise inactivation of chlorine compounds. Approximately 38% of the Caucasian population exhibit a homozygous deletion of the gene (GST-T1*0/*0) and thus do not express any enzyme.

GST-M1 detoxifies numerous electrophilic metabolites. Specific substrates include dichloro-nitrobenzene and stilbene oxide. Approximately half of the Caucasian population exhibits a homozygous deletion of the gene (GST-M1*0/*0) and therefore does not express any enzyme.

GST-P1 is involved in the metabolism of several drugs and their metabolites (acetaminophen, ifosfamide, thiotepa). The p.I105V variant in the GST-P1 gene has been associated with a reduced enzyme activity. Approx. 50% of the population are homozygous for the isoleucine variant; approx. 40% are heterozygous for Ile/Val105 and approximately 10% are homozygous for the Valin allele.

The metabolism of xenobiotics in the body usually involves several steps with several enzyme systems being involved. In the intermediate stages of the detoxification process, toxic metabolites can occur. In many cases, the route of degradation with all its enzyme systems involved has not entirely been characterized yet. Therefore, the analysis of the GST genotypes only provides partial information on the toxification capacity of the patient.