Leukotrienes in Hepatocyte Injury.
Trudell JR; Gut J; Costa AK
Modulation of Liver Cell Expression, Proceedings of the 43rd Falk Symposium, Basel, October 14-15, MTP Press Limited, Lancaster 1987:411-421
Studies of the metabolism of the leukotriene-B4 (LTB4) under varying oxygen concentrations were performed in confluent cultures of hepatocyte monolayers, in order to expose all the hepatocytes in a particular experiment to exactly the same concentration of oxygen. The metabolism of hepatocyte monolayers of nanomolar concentrations of LTB4 was examined under physiologically relevant oxygen tensions. Findings were discussed for the incubation of leukotriene-A4 (LTA4) with human liver microsomes, the inhibition of LTB4 formation by cytochrome-P-450, LTB4 receptor binding assay, the mechanism of LTA4 hydrolysis, conformational analysis of LTA4 and LTB4, reduction of LTB4 metabolism by hypoxia and the balance of hepatic formation and metabolism of LTB4. The finding in this study that LTB4 metabolism did not reach saturation even at 740 nanomoles/liter (nmol/l) demonstrated that the normoxic liver has the capacity to deal with instantaneous pulses of LTB4 formation and/or systemic releases that far exceed the 1 to 10nmol/l concentrations that have been measured in blood. Hepatic hypoxia may result in failure to remove circulating LTB4 from the blood. Under hypoxia, reductive metabolism of the hepatotoxic agents resulted in the generation of free radicals. Transformation of 5-hydroperoxyeicosatetraenoic-acid to LTB4 in hepatocytes, particularly at low oxygen concentrations, may constitute an important mechanism of liver injury. The presence of LTB4 in a hepatocyte could result in chemoattraction and activation of both Kupffer cells and circulating phagocytes.
NIOSH-Grant; Grants-other; Hepatotoxicity; Liver-enzymes; Metabolic-study; Allergic-reactions; Fatty-acids; In-vitro-studies; Humans;
Anesthesia Stanford University Department of Anesthesia Stanford, Calif 94305
Other Occupational Concerns; Grants-other;
Modulation of Liver Cell Expression, Proceedings of the 43rd Falk Symposium, Basel, October 14-15, MTP Press Limited, Lancaster
Stanford University, Stanford, California