Glutathione-linked enzymes in normal and tumor cells and their role in resistance against genotoxic agents.
Glutathione is the most abundant low molecular mass thiol in human cells. It is involved in the inactivation of genotoxic electrophilic compounds, and a variety of glutathione-linked enzymes catalyze such detoxication reactions. Within this group, the enzymes occurring in highest intracellular concentrations are the glutathione transferases, which catalyze the detoxication of a broad spectrum of alkylating and oxidizing compounds such as epoxides, reactive alkenes and organic hydroperoxides. Multiple forms of glutathione transferase with distinct substrate specificities exist, and their differential expression in cells contributes to differences in detoxication capacities in tissues. Glyoxalase I catalyzes the inactivation of 2-oxoaldehydes and may also be considered as part of the cellular detoxication system. Characterization of the different enzymes and their differential expression in normal and tumor cells will help to clarify their cellular functions and their significance to human cancer. Clear differences in the occurrence of the various enzyme forms in normal and tumor cells have been demonstrated and variations between different tumors appear to be linked to their degree of resistance to alkylating cytostatic drugs. Modulation of catalytic activities in vitro by administration of enzyme inhibitors may help to overcome this resistance.
Mannervik
B
B
Department of Biochemistry, Uppsala University, Biomedical Center, Uppsala, Sweden.
Berhane
K
K
Castro
V M
VM
Olin
B
B
Ridderström
M
M
Vignani
R
R
Kozarich
J W
JW
Ringborg
U
U
D000818:Animals; D000970:Antineoplastic Agents / Q000276:immunology*; D001483:Base Sequence; D004351:Drug Resistance / Q000502:physiology*; D005091:Exons / Q000235:genetics; D005982:Glutathione Transferase / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007791:Lactoylglutathione Lyase / Q000276:immunology*; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000201:enzymology* / Q000276:immunology; D011110:Polymorphism, Genetic; D051381:Rats
D000970:Antineoplastic Agents; D005982:Glutathione Transferase; D007791:Lactoylglutathione Lyase