FREQUENT COEXPRESSION OF MRP GS-X PUMP AND GAMMA-GLUTAMYLCYSTEINE SYNTHETASE MESSENGER-RNA IN DRUG-RESISTANT CELLS, UNTREATED TUMOR-CELLS, AND NORMAL MOUSE-TISSUES/

Expression of the multidrug-resistance protein gene MRP, which confers non-P-glycoprotein-mediated multidrug resistance, has been found in m any drug-resistant variants and tumor samples. Recent studies have dem onstrated that MRP functions as an ATP-dependent transporter functiona lly related to the previously described glutathione-conjugate (GS-X) p ump. We have shown recently that the MRP and gamma-glutamylcysteine sy nthetase (gamma-GCS) heavy subunit mRNA levels are coordinately overex pressed in cisplatin (CP)-resistant human leukemia cells (Ishikawa et al.,] Biol Chem 271: 14981-14988, 1996) and frequently co-elevated in human colorectal tumors (Kuo et al., Cancer Res 56: 3642-3644, 1996). In the present study, we showed the coexpression patterns of thirteen additional human drug-resistant cell lines representing different tumo r cell origins selected with different agents, except for one doxorubi cin-selected line which demonstrated minor elevation in MRP mRNA with no detectable increase in gamma-GCS mRNA, suggesting that the increase of MRP mRNA preceded the increase in gamma-GCS mRNA. Furthermore, in seventeen randomly selected untreated tumor cell lines, the overall co rrelation coefficient between MRP and gamma-GCS mRNA levels was 0.861. In normal mice, the correlation coefficient of mrp and gamma-gcs mRNA was 0.662 in fourteen tissues (kidney and liver were not included) an alyzed. Kidney and liver expressed low levels of mrp relative to gamma -gcs; however, these two tissues expressed high levels of a functional ly related mrp homologue, mrp2 (cMoat or cMrp), which may have compens ated for the underexpressed mrp in maintaining the total GS-X pump act ivities. Altogether, these results demonstrated the frequent coexpress ion of these two genes in various cell settings. (C) 1998 Elsevier Sci ence Inc.