Expression of anionic glutathione-S-transferase and P-glycoprotein genes in human tissues and tumors.
The development of multidrug resistance in MCF-7 human breast cancer cells and the acquisition of broad resistance to xenobiotics in rat hyperplastic nodules are both associated with increased P-glycoprotein (mdr) gene expression as well as changes in activities of intracellular detoxication enzymes; among these changes is a significant increase in the activity of the anionic isozyme of glutathione-S-transferase (GST). We have isolated a cDNA encoding the human anionic glutathione-S-transferase, GST pi-1, from a cDNA library constructed from multidrug-resistant MCF-7 cells. The deduced amino acid sequence of GST pi-1 shows that while the human anionic GST displays 85% nucleotide and amino acid sequence homology to the rat anionic isozyme, it is markedly less related to human basic GST isozymes. We have examined the expression of GST pi and P-glycoprotein in 170 specimens of human tissues and tumors. P-Glycoprotein RNA expression was positive in eight of 23 lymphomas and two of 12 colon tumors; however, many other normal and malignant tissues, including lung, bladder, and breast tumors, had low or undetectable levels of P-glycoprotein RNA expression. In contrast, GST pi was readily detected in a wide variety of normal and malignant tissues. The level of GST pi mRNA expression in normal tissues was heterogeneous, with lowest levels found in liver and the highest levels found in lung, esophagus, and placenta. GST pi was also variably expressed in human tumors, with the lowest relative levels occurring in lymphoma and breast cancer and the highest levels found in lung cancer and head and neck tumors. In addition, comparison of paired specimens from the same patient indicated that GST pi expression was increased in many tumors relative to matched normal tissue.
Moscow
J A
JA
Medicine Branch, National Cancer Institute, Bethesda, Maryland 20892.
Fairchild
C R
CR
Madden
M J
MJ
Ransom
D T
DT
Wieand
H S
HS
O'Brien
E E
EE
Poplack
D G
DG
Cossman
J
J
Myers
C E
CE
Cowan
K H
KH
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001483:Base Sequence; D004247:DNA / Q000032:analysis; D004351:Drug Resistance; D005786:Gene Expression Regulation; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D007527:Isoenzymes / Q000235:genetics*; D008562:Membrane Glycoproteins / Q000235:genetics*; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000032:analysis*; D012313:RNA / Q000032:analysis*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D007527:Isoenzymes; D008562:Membrane Glycoproteins; D012313:RNA; D004247:DNA; D005982:Glutathione Transferase