| Though the expression and important role of cytochrome P-450 in the xenobiotic metabolism in the term placenta of smokers are known, the presence of either cytochrome P-450 or prostaglandin synthase is questionable in the term placenta of nonsmokers. Information is lacking regarding the involvement of alternative enzymatic pathway(s) in xenobiotic metabolism and bioactivation in nonsmokers' placenta leading to cytotoxicity. Thus, the aim of this study was to test the hypothesis that lipoxygenase (LO) plays a significant role in the metabolism of xenobiotics in nonsmokers' placenta. This may provide an important clue in the understanding of teratogenicity/transplacental carcinogenicity of chemicals in humans.; Reverse phase HPLC analysis detected the presence of 5-, 12- and 15-HETE upon incubation of arachidonic acid with affinity purified human term placental LO, free of hemoglobin. This result indicates that a mixture of LO isozymes is present in the affinity purified enzyme preparations from term placenta of nonsmokers. This enzyme sample was also used to study the co-oxidative potential of LO.; The ability of human term placental LO in the co-oxidation of aflatoxin B{dollar}sb1{dollar} as evidenced by tris-diol formation and in subsequent covalent binding to DNA were clearly demonstrated. The optimum rate of all-trans retinol acetate co-oxidation was measured spectrophotometrically by monitoring the reaction kinetics during its depletion at 330 nm. 4-aminobiphenyl co-oxidation was also analyzed by monitoring the spectral changes during its disappearance at 270 nm and a gradual appearance of a new peak at 315 nm, indicating a metabolite formation. Both reverse phase HPLC and GC-MS analysis identified 4,4{dollar}spprime{dollar}-azobis(biphenyl) as an oxidative metabolite of 4-aminobiphenyl. All the co-oxidation reactions discussed above were inhibited by LO inhibitors, showing the involvement of LO in the xenobiotic co-oxidation and bioactivation in human term placenta of nonsmokers.; Similar observations were noted during xenobiotic oxidation catalyzed by LO affinity purified from human intrauterine conceptual tissues at early (8-10) weeks of gestation. Significant dioxygenase activity and co-oxidase activity towards benzidine and its analogs and aflatoxin B{dollar}sb1{dollar} were observed. Aflatoxin B{dollar}sb1{dollar} was also bioactivated in the presence of same enzyme preparations. These reactions were inhibited by known LO inhibitors suggesting clearly the participation of LO in xenobiotic metabolism during early human pregnancy. |
