Abstract

P-glycoprotein (Pgp), a drug transport protein, pumps many drugs out of hepatocytes. To begin to determine how variation in the level of human hepatic Pgp might influence individual differences in drug disposition, we have used Northern blot and immunochemical analysis to determine the variation in Pgp and in the mRNA for Pgp (MDR1) in liver from 41 individuals. These samples were divided into two groups, normal and perineoplastic (normal liver adjacent to secondary hepatic neoplasms). There was large variation in MDR1 mRNA and Pgp protein expression between all human liver samples. The average amount of Pgp was 2.5-fold greater in normal than in perineoplastic liver. Hepatic Pgp expression was associated with gender, with males expressing 2-fold higher amounts of Pgp than females. There was no correlation between expression of MDR1 and cytochrome P4501A1, but there was a trend toward Pgp and cytochrome P4503A proteins being inversely correlated, although it did not reach statistical significance. MDR1 expression was increased in three 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 month postnatally. The level of Pgp was then compared between nine paired samples consisting of seven secondary metastatic hepatic neoplasms, one primary heptocellular carcinoma, one hepatic adenoma and their adjacent normal perineoplastic liver. There was no consistent increase or decrease in Pgp expression in secondary hepatic neoplasms compared with paired perineoplastic liver.(ABSTRACT TRUNCATED AT 250 WORDS)