Denis M. Bailey

Chapter 20. Arachidonate Lipoxygenase

Publisher Summary Lipoxygenases are enzymes that catalyze the hydroperoxidation of polyunsaturated fatty acids, esters, alcohols, and others containing a cis-cis-1,4-pentadiene system; the products contain 1-hydroperoxy-2,4-trans, cispentadiene fragments. The enzymes belong to the class known as dioxygenases that characteristically incorporate two atoms of molecular oxygen into a substrate. It was found in 1974 that Guinea pig lung and spleen homogenates produced at least ten times as much 12-hydroxyeicosatetraenoic acid (HETE) when incubated with AA as did homogenates of kidney, stomach, liver, heart, and whole blood. The term arachidonate lipoxygenase was coined shortly hereafter when the enzyme isolated from platelets of various mammals displayed higher conversion rates for AA than for a variety of other fatty acids containing the cis-cis-1,4-pentadiene fragment. Dihydroxyeicosatetraenoic acids (di-HETEs) were isolated after the incubation of suspensions of rabbit peritoneal polymorphonuclear leucocytes (PMNL) with AA and the unstable (leukotriene A 4 ) was proposed as the reactive intermediate. In addition to human platelets, guinea pig lung and spleen homogenates, rabbit PMNL, human neutrophil, and rat RBL-1 cells, other tissues have been reported to display lipoxygenase activity against a variety of substrates. Researchers examined a large list of flavonoids for the inhibition of lipoxygenase from soybean, from rat lung, and spleen and for the inhibition of PG synthetase from rat renal medulla. A comparison of 27 and 1,5-dihydroxynaphthalene, using plant and rat lipoxygenases, shows almost identical inhibition properties, adding evidence that most soybean lipoxygenase inhibitors inhibit animal lipoxygenase as well.

Activity of quinfamide against natural infections of Entamoeba criceti in hamsters: a new potent agent for intestinal amoebiasis

A novel tetrahydroquinolinyl ester, quinfamide, administered orally in multiple doses for 3 days had an ED50 of 0.25 mg/kg/day (total dose 0.75 mg/kg) for eradicating Entamoeba criceti in hamsters in several tests. It was significantly more active by direct comparison than 3 commercially available amoebicides and at least as active as 2 other esters of the parent compound, 1-(dichloroacety)-1,2,3,4-tetrahydro-6-quinolinol. After administration of a single dose, ED50 calculations for quinfamide averaged 0.9 mg/kg. Quinfamide was considerably more active than the other tetrahydroquinolinols, diloxanide furoate and teclozan, and it was approximately 1.5 times more active than etofamide; a statistical significance between the latter 2 drugs could be demonstrated in one of 4 tests. Administered prophylactically, quinfamide was shown to protect hamsters from re-infection with E. criceti. It also inhibited propagation of E. histolytica in vitro at a concentration of 20 microgram/ml. No adverse effects were noted in rodents after a single dose as high as 10 g/kg. Daily administration to monkeys of doses up to 500 mg/kg for as long as 37 days produced no pharmacological aberrations during or after medication; haematological studies and urine analyses were normal and no gross or microscopical tissue changes attributable to quinfamide were observed. No toxicity was revealed following acute (2 g/kg) and chronic (500 mg/kg/day x 31 days) administration of the drug to dogs and rats, respectively.