HIGH-LEVEL EXPRESSION OF THE MULTIDRUG-RESISTANCE (MDRI) GENE IN THE NORMAL BLADDER UROTHELIUM - A POTENTIAL INVOLVEMENT IN PROTECTION AGAINST CARCINOGENS

It has been suggested that expresssion of the P-glycoprotein transmemb rane efflux pump (PGP), encoded by the multidrug resistance (MDR1) gen e, may play a role in the protection of epithelial tissues from a vari ety of local and systemic toxins, We report that in similar to 50% (6/ 11) of the population, MDR1 messenger RNA levels in the normal urinary epithelium are comparable to those found in the highest expressing ti ssues in the body, and suggest a role for PGP in the normal bladder ur othelium. MDR1 mRNA levels in the normal urothelium do, however, vary over a 60-fold range between individuals, and furthermore are uniforml y significantly lower (similar to 6-fold, P less than or equal to 0.01 ) in all low-grade bladder carcinoma samples, On the basis of these ob servations we conclude that low MDR1 mRNA levels are a uniformly consi stent characteristic of low-grade bladder tumours, and hypothesize tha t high MDR1 expression plays a role in protection of the normal bladde r from carcinogen exposure, and that individuals with low normal bladd er MDR1 mRNA levels may consequently be at an increased risk of develo ping bladder cancer, Furthermore, the low level of MDR1 expression gen erally found in low grade superficial tumours may predispose them to a dditional carcinogen exposure and in this way contribute to possible t umour progression, In addition, MDR1 mRNA levels were observed to be e levated in a significant proportion (similar to 25%, 8/30, P = 0.015) of high grade tumours compared to low grade samples, and may therefore represent a marker of bladder tumour progression.