INTERINDIVIDUAL VARIATION IN EXPRESSION OF P-GLYCOPROTEIN IN NORMAL HUMAN LIVER AND SECONDARY HEPATIC NEOPLASMS

beta-glycoprotein (Pgp), a drug transport protein, pumps many drugs ou t of hepatocytes. To begin to determine how variation in the level of human hepatic Pgp might influence individual differences in drug dispo sition, we have used Northern blot and immunochemical analysis to dete rmine the variation in Pgp and in the mRNA for Pgp (MDR1) in liver fro m 41 individuals. These samples were divided into two groups, normal a nd perineoplastic (normal liver adjacent to secondary hepatic neoplasm s). There was large variation in MDR1 mRNA and Pgp protein expression between all human liver samples. The average amount of Pgp was 2.5-fol d greater in normal than in perineoplastic liver. Hepatic Pgp expressi on was associated with gender, with males expressing 2-fold higher amo unts of Pgp than females. There was no correlation between expression of MDR1 and cytochrome P4501A1, but there was a trend toward Pgp and c ytochrome P4503A proteins being inversely correlated, although it did not reach statistical significance. MDR1 expression was increased in t hree of four individuals who had previously received chemotherapy. Pgp expression appeared to be regulated developmentally as MDR1 mRNA was undetectable in six fetal livers, but Pgp was present as early as 1 mo nth postnatally. The level of Pgp was then compared between nine paire d samples consisting of seven secondary metastatic hepatic neoplasms, one primary heptocellular carcinoma, one hepatic adenoma and their adj acent normal perineoplastic liver. There was no consistent increase or decrease in Pgp expression in secondary hepatic neoplasms compared wi th paired perineoplastic liver. However, the median amount of Pgp in a ll neoplasms was reduced to 75% of the median amount in the paired per ineoplastic samples. We conclude that there is large interindividual v ariation in hepatic content of Pgp which likely contributes to individ ual variation in the drug disposition of Pgp substrates.