Title
Increased bioactivation of dihaloalkanes in rat liver due to induction of class Theta glutathione S-transferase T1-1
Author
Sherratt, P.J.
Manson, M.M.
Thomson, A.M.
Hissink, E.A.M.
Neal, G.E.
van Bladeren, P.J.
Green, T.
Hayes, J.D.
Centraal Instituut voor Voedingsonderzoek TNO
Publication year
1998
Abstract
A characteristic feature of the class Theta glutathione S-transferase (GST) T1-1 is its ability to activate dichloromethane and dibromoethane by catalysing the formation of mutagenic conjugates. The level of the GSTT1 subunit within tissues is an important determinant of susceptibility to the carcinogenic effects of these dihaloalkanes. In the present study it is demonstrated that hepatic GST activity towards these compounds can be elevated significantly in female and male Fischer-344 rats by feeding these animals on diets supplemented with cancer chemopreventive agents. Immunoblotting experiments showed that increased activity towards the dihaloalkanes is associated with elevated levels of the GSTT1 subunit in rat liver. Sex-specific effects were observed in the induction of GSTT1 protein. Amongst the chemopreventive agents tested, indole-3-carbinol proved to be the most potent inducer of hepatic GSTT1 in male rats (6.2-fold), whereas coumarin was the most potent inducer of this subunit in the livers of female rats (3.5-fold). Phenobarbital showed significant induction of GSTT1 only in male rat liver and had little effect in female rat liver. Western blotting showed that class Alpha, Mu and Pi GST subunits are not co-ordinately induced with GSTT1, indicating that the expression of GSTT1 is determined, at least in part, by mechanisms distinct from those that regulate levels of other transferases. The increase in amount of hepatic GSTT1 protein was also reflected by an increase in the steady-state level of mRNA in response to treatment with chemopreventive agents and model inducers. Immunohistochemical detection of GSTT1 in rat liver supported the Western blotting data, but showed, in addition to cytoplasmic staining, significant nuclear localization of the enzyme in hepatocytes from some treated animals, including those fed on an oltipraz containing diet. Significantly, the hepatic level of cytochrome P450 2E1, an enzyme which offers a detoxification pathway for dihaloalkanes, was unchanged by the various inducing agents studied. It is concluded that the induction of GSTT1 by dietary components and its localization within cells are important factors that should be considered when assessing the risk dihaloalkanes pose to human health.
Subject
Nutrition
3 indolemethanol
Alkane derivative
Antineoplastic agent
Cytochrome p450
Glutathione transferase
Liver enzyme
Messenger rna
Phenobarbital
Animal tissue
Cancer prevention
Chemoprophylaxis
Controlled study
Cytoplasm
Diet
Enzyme subunit
Female
Immunoblotting
Male
Nonhuman
Priority journal
Rat
Animals
Anticarcinogenic Agents
Biotransformation
Carcinogens
Dietary Supplements
Enzyme Induction
Female
Glutathione Transferase
Humans
Hydrocarbons, Brominated
Isoenzymes
Liver
Male
Methylene Chloride
Phenobarbital
Rats
Rats, Inbred F344
Sex Characteristics
Xenobiotics
Animalia
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TNO identifier
234666
ISSN
0264-6021
Source
Biochemical Journal, 335 (3), 619-630
Document type
article