Rat Hepatocytes Generate Peptide Leukotrienes from Leukotriene A4

The biosynthetic mechanism of peptide leukotrienes was studied in rat liver. A catalytic activity to synthesize leukotriene (LT) C4 from LTA4 (LTC4 synthesis activity) was shown to be associated mainly with the microsomal fraction of hepatocytes, but also to a small extent with nonparenchymal cells including Kupffer cells, suggesting that the hepatocytes have an ability to generate peptide LTs. Stimulation of the isolated hepatocytes with calcium ionophore (A23187) did not cause any significant production of peptide LTs, whereas addition of LTA4 induced a remarkable generation of peptide LTs in a dose-dependent manner. Addition of LTA4 also augmented the pep-tide LT production by Kupffer cells, but its amount was much smaller than that by the hepatocytes under the same culture conditions. Coincubation of the hepatocytes and Kupffer cells, following A23187 stimulation, elicited a markedly enhanced production of peptide LTs even without any addition of LTA4, whereas the LT production in the coincubation system was suppressed almost completely by treating the Kupffer cells with a specific inhibitor of 5-lipoxygenase, AA861 (10 μM). An enzymatic cooperation between the hepatocytes and Kupffer cells may play an important role in generating peptide LTs in the liver.