Effect of lindane and phenobarbital on cyclooxygenase-2 expression and prostanoid synthesis by Kupffer cells

Prostaglandins (PGs) have been implicated in tumor promotion. In this study , we investigated the effect of the hepatic tumor promoters lindane and phe nobarbital (PB) on the PG metabolism of Kupffer cells in vitro and in vivo, in particular on the expression of cyclooxygenase (COX), the leading enzym e in prostanoid synthesis. Exposure of primary cultures of Kupffer cells to lindane for 1 h stimulated the production of the PGs PGE(2) and PGD(2) mar kedly (up to 50-fold) and that of PGF(2 alpha) by >3-fold. This effect was accompanied by an increase in the COX-2 protein, as demonstrated by western blotting. Similarly, PB, which shares several effects with lindane in rat liver, also clearly induced COX-2, Lindane and PB affected the PG synthesis in vitro and in vivo in Kupffer cells of rats that had been treated with t he two compounds for 56 days. Kupffer cells, which were isolated at days 2, 5 and 56 of the treatment, showed a significant increase in the levels of COX-2 mRNA and protein. Total COX activity was increased similar to 2-fold and 3- to 5-fold in Kupffer cell homogenates of PB- and lindane-treated ani mals, respectively, compared with the untreated controls. These results sug gest that paracrine mechanisms may contribute to the tumor-promoting activi ty of lindane and PB, stimulating the production of PGs by Kupffer cells.