Carcinogenesis, Vol. 20, No. 8, 1411-1416,
August 1999
© 1999 Oxford University Press
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Effect of lindane and phenobarbital on cyclooxygenase-2 expression and prostanoid synthesis by Kupffer cells
GSF-National Research Center for Environment and Health, Institute of Toxicology, D-85758 Neuherberg/München and
1 University of Marburg, Department of Pediatrics, 35037 Marburg, Germany
Prostaglandins (PGs) have been implicated in tumor promotion. In this study, we investigated the effect of the hepatic tumor promoters lindane and phenobarbital (PB) on the PG metabolism of Kupffer cells in vitro and in vivo, in particular on the expression of cyclooxygenase (COX), the leading enzyme in prostanoid synthesis. Exposure of primary cultures of Kupffer cells to lindane for 1 h stimulated the production of the PGs PGE2 and PGD2 markedly (up to 50-fold) and that of PGF2
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 the 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 ~2-fold and 3- to 5-fold in Kupffer cell homogenates of PB- and lindane-treated animals, respectively, compared with the untreated controls. These results suggest that paracrine mechanisms may contribute to the tumor-promoting activity of lindane and PB, stimulating the production of PGs by Kupffer cells.
Abbreviations: AA, arachidonic acid; COX, cyclooxygenase (prostaglandin H-synthase); DTT, dithiothreitol; DMEM, Dulbeco's modified Eagle's medium; lindane, 
-hexachlorocyclohexane; PB, phenobarbital; PGs, prostaglandins; RT–PCR, reverse transcriptase–polymerase chain reaction
2 To whom correspondence should be addressed Email: schwarz{at}gsf.de
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