Direct comparison of the nature of mouse and human GST T1-1 and the implications on dichloromethane carcinogenicity.
Dichloromethane (DCM) is a hepatic and pulmonary carcinogen in mice exposed to high doses by inhalation. It has been shown previously that the incidence of liver and lung tumors does not increase in rats or hamsters exposed to the dihaloalkane under conditions similar to those that produced tumors in mice. The biological consequences of DCM exposure to humans is therefore uncertain. The carcinogenic effects of DCM in the mouse are caused by the interaction with DNA of a glutathione (GSH) conjugate that is produced by the class theta glutathione S-transferase T1-1 (GST T1-1). The species specificity is thought to be due to the greater amount of transferase activity in mouse target organs and specific nuclear localization of GST T1-1 in target cells. This paper directly compares the relative capacity and locality of DCM activation in mouse and human tissues. The results show that mouse GST T1-1 is more efficient in catalyzing the conjugation of DCM with GSH than the orthologous human enzyme. In addition, the mouse expresses higher levels of the transferase than humans in hepatic tissue. Histochemical analysis confirmed the presence of GST T1-1 in the nucleus of mouse liver cells. However, in human liver GST T1-1 was detected in bile duct epithelial cells and hepatocyte nuclei but was also present in the cytoplasm. Taking this information into account, it is unlikely that humans have a sufficiently high capacity to activate DCM for this compound to be considered to represent a carcinogenic risk.
Sherratt
Philip J
PJ
Biomedical Research Centre, University of Dundee, Ninewells Hospital and Medical School, Dundee, Scotland, DD1 9SY, United Kingdom.
Williams
Sally
S
Foster
John
J
Kernohan
Neil
N
Green
Trevor
T
Hayes
John D
JD
D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D002384:Catalysis; D004591:Electrophoresis, Polyacrylamide Gel; D004926:Escherichia coli / Q000378:metabolism; D005982:Glutathione Transferase / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D007202:Indicators and Reagents; D007700:Kinetics; D008099:Liver / Q000201:enzymology*; D008752:Methylene Chloride / Q000633:toxicity*; D051379:Mice; D008815:Mice, Inbred Strains; D011994:Recombinant Proteins / Q000737:chemistry; D013045:Species Specificity
D002273:Carcinogens; D007202:Indicators and Reagents; D011994:Recombinant Proteins; D008752:Methylene Chloride; C413545:glutathione S-transferase T1; D005982:Glutathione Transferase