Elevated expression of hepatic proliferative markers during early hepatocarcinogenesis in hepatitis-B virus transgenic mice lacking mdr1a-encoded P-glycoprotein

Recent studies have shown that expression levels of the multidrug resistanc e gene MDR1, which encodes the drug transporter P-glycoprotein, correlate w ith prognostic outcomes of certain tumor types. These findings suggest that expression of MDR1 may affect tumor behaviors. To address this issue furth er, we investigated the expression of mdr1a, a human MDR1 homolog, on the d evelopment of hepatocellular carcinoma in a transgenic mouse model carrying the liver-targeted expression of human hepatitis-B virus (HBV) surface ant igen. The pathogenetic program was compared in HBV mice carrying either mdr 1a(+/+) or mdr1a(-/-). We found that the expressions of proliferative activ ity markers, Ki67 nuclear antigen, and proliferating cell nuclear antigen w ere elevated in mdr1a(-/-) mice younger than 10 wk in comparison with those in the same age group of wild-type animals. Replication in the hepatic pop ulation as determined by bromodeoxyuridine incorporation tended to support observation that mdr1a(-/-) mice exhibited elevated labeling indices in thi s age group. Moreover, histologic staining and flow-cytometric analysis sho wed that the mdr1a(-/-) animals exhibited a higher cell population with pol yploidy than did the mdr1a(+/+) counterparts of the same age. However, no s ignificant differences in the expression of the liver-injury markers serum alanine transaminase and aspartate transaminase were observed. Although our results showed that absence of mdr1a expression is correlated with modest enhanced proliferative characteristics in the livers at stage before the de velopment of hepatocellular carcinoma, the overall life spans between these two strains of mice were not significantly different. The implication of t hese findings to the role of P-glycoprotein in tumor development and cancer chemotherapy is discussed. Mol. Carcinog. 29: 103-111, 2000. (C) 2000 Wile y-Liss, Inc.