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Metabolism of Xenobiotics (Overview)

OMIM numbers: 134660 (GSTP1), 138350 (GSTM1), 600436 (GSTT1), 612182 (NAT2), 108330 (CYP1A1), 124060 (CYP1A2)

Dipl.-Biol. Birgit Busse

Scientific Background

Various classes of enzymes are involved in the detoxification of xenobiotics in the human organism. From the perspective of occupational medicine, the analysis of the classes of enzymes is of interest regarding exposition to xenobiotics as well as concerning persons with unclear reactions to environmental toxins.

GST: Glutathione S-transferases (GSTs) are multifunctional enzymes that play a key role in the cellular detoxification. There are different GST classes (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 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.

NAT2: The detoxification of xenobiotics by the acetylation of various functional groups in the human organism is catalyzed by the N-acetyltransferases NAT1 and NAT2. Substrates of NAT2 are aromatic amines (e.g. naphthylamine or benzidine) as well as drugs (e.g. isoniazid, sulfonamides or hydralazine). Different polymorphisms in the NAT2 gene lead to a rapid or slow acetylation capacity. Approx. 70% of the Caucasian population are slow acetylators.

CYP1A1: Cytochrome P450-1A1 (CYP1A1) belongs to the group of phase I enzymes and facilitates the degradation of environmental toxins such as polycyclic aromatic hydrocarbons (PAHs) and different xenobiotics. Approximately 10% of the Caucasian population exhibit an increased inducibility of the enzyme due to genetic polymorphisms.

CYP1A2: CYP1A2 is involved in the metabolism of a range of environmental toxins such as aromatic and heterocyclic amines and several drugs. The CYP1A2 enzyme system can be induced by various substances (e.g. cigarette smoke). A wide range of variants in the CYP1A2 gene are known that have been associated with altered enzyme activity. The clinical relevance of these variants in vivo has not entirely been clarified yet; therefore the analysis of the gene is currently not part of routine diagnostics and is only conducted on special request and after consultation.

The metabolism of xenobiotics in the body usually involves several steps with several enzyme systems being involved. In many cases, the route of degradation with all its enzyme systems involved has not entirely been characterized yet. Therefore, the analysis of the listed genes only provides partial information on the detoxification capacity of the patient.