Thromboxane B 2 uptake and metabolism in isolated perfused lung identification and comparison with prostaglandin F 2α

Abstract

Thromboxane B 2 was metabolised in isolated perfused guinea-pig lungs to a product identified by negative ion chemical ionisation mass spectrometry as 13,14-dihydro-15-ketothromboxane B 2. Conversion was measured by radio TLC and was greater in guinea-pig than rat lungs (29.1 vs. 13.8% at 10 ng/ml), but similar in lungs from normal and sensitized guinea-pigs. Thromboxane B 2 metabolism was less than that of prostaglandin F 2α but, like it, was prevented at 5°C and reduced by cycloheximide pretreatment. Tissue to medium ratio in perfused guinea-pig lungs was 3.4 for thromboxane B 2, but 0.2 for inulin (showing that thromboxane B 2 is accumulated within the lung) and was altered after experimental manipulations. Neither lung slices, crude homogenates, cytosolic and microsomal fractions nor purified prostaglandin 15-hydroxydehydrogenase metabolised thromboxane B 2 in vitro, although prostaglandin F 2α was extensively inactivated. Quantitative partition coefficient and albumin-binding data confirm that thromboxane B 2 lacks prominent lipophilicity, implying that cellular uptake in lung must be carrier-mediated. We conclude that thromboxane B 2 is a substrate for pulmonary degradation which may form a route for the biological inactivation of thromboxane A 2. Its resistance to prostaglandin 15-hydroxydehydrogenase as conventionally tested remains paradoxical and is discussed.