Evidence for Lipoxygenase-Catalyzed Bioactivation of Phenytoin to a Teratogenic Reactive Intermediate: In Vitro Studies Using Linoleic Acid-Dependent Soybean Lipoxygenase, and in Vivo Studies Using Pregnant CD-1 Mice

Lipoxygenase - a versatile biocatalyst for biotransformation of endobiotics and xenobiotics

“…Phenytoin, a known human teratogen, is used during pregnancy as an efficacious anticonvulsant. The relevance of maternal and embryonic P450 in its bioactivation has been questioned [96,97]. SLO-mediated PUFAdependent oxidation of phenytoin to free-radical species is accompanied by covalent binding to proteins which can be suppressed by the classical LO inhibitors [96,97].…”

“…The relevance of maternal and embryonic P450 in its bioactivation has been questioned [96,97]. SLO-mediated PUFAdependent oxidation of phenytoin to free-radical species is accompanied by covalent binding to proteins which can be suppressed by the classical LO inhibitors [96,97]. Cyclophosphamide is a prodrug whose toxicity and therapeutic efficacy depends on its metabolic activation.…”

The Non-steroidal Anti-inflammatory Drugs Protect Mouse Cochlea against Acoustic Injury

“…AA is oxidized by COX to form PGG2, which is subsequently transformed by hydroperoxidase to form PGH2. As ROS are produced during the conversion of PGG2 to PGH2 (Yu and Wells 1995), ROS production is inhibited by COX inhibitors. Similarly, LOX oxidizes AA to form hydroperoxy-eicosatetraenoic acid (HPETE).…”

“…Similarly, LOX oxidizes AA to form hydroperoxy-eicosatetraenoic acid (HPETE). Subsequently, HPETE is converted to hydroxy-eicosatetraenoic acid (HETE) by hydroperoxidase, and again ROS are produced during the conversion of HPETE to HETE (Yu and Wells 1995). COX and LOX inhibitors thus block ROS production and these actions might account for the protective mechanism of COX and LOX inhibitors.…”

Isolation and some properties of dioxygenase and co-oxidase activities of adult human liver cytosolic lipoxygenase

“…Available evidence suggests that NAD(P)H (32), glutathione (33), ascorbate (34), vitamin E (35), proline (36), catecholamines (37), and possibly other chemicals serve as the endogenous substrates for the co-oxidase activity of various LOs. Among xenobiotics, it is now known that several model hydrogen donors (38), hepatotoxicants (39), drugs (40,41), pesticides (42,43), industrial and environmental chemicals (44), carcinogens (44)(45)(46)(47), and other chemicals (5) are co-oxidized by the LO system. The mammalian tissue LOs exhibiting co-oxidase activity include those isolated from liver (27,45,46), brain (2,37,43), lung (3), placental (4,41,44,47), and embryonic or fetal tissues (5,47).…”