PHENOTYPIC VARIABILITY IN INDUCTION OF P-GLYCOPROTEIN MESSENGER-RNA BY AROMATIC-HYDROCARBONS IN PRIMARY HUMAN HEPATOCYTES

To determine whether human liver responds to treatment with aromatic h ydrocarbons (AHs) with induction of the multidrug resistance (mdr) gen e product P-glycoprotein and whether AH induction of mdr involves the Ah receptor, we compared induction of mdr mRNA with induction of cytoc hrome P450 (CYP)1A1 mRNA in AH-treated cultures of primary human hepat ocytes. Hepatocytes from all 15 individuals tested responded to treatm ent with 3-methylcholanthrene (MC) or 2,3,7,8-tetrachlorodibenzo-p-dio xin (TCDD) with induction of CYP1A1 mRNA. However, only 62% and 55% of the preparations responded to treatment with MC and TCDD, respectivel y, with induction of mdr mRNA. Indeed, in some individuals mdr mRNA wa s suppressed by MC and TCDD despite robust CYP1A1 induction. These stu dies provide the first evidence that not only does individual variatio n in mdr induction by AH exist but that AHs regulate mdr in humans by a novel mechanism distinguishable from the classical Ah receptor pathw ay. The dramatic variability in AH induction of mdr may be a predictiv e risk factor that will help to identify an individual's risk of AH-as sociated toxicities. (C) 1995 Wiley-Liss, Inc.