Involvement of Cytochrome P450 in Reactive Oxygen Species Formation and Cancer.

This review examines the involvement of cytochrome P450 (CYP) enzymes in the formation of reactive oxygen species in biological systems and discusses the possible involvement of reactive oxygen species and CYP enzymes in cancer. Reactive oxygen species are formed in biological systems as byproducts of the reduction of molecular oxygen and include the superoxide radical anion (∙O2-), hydrogen peroxide (H2O2), hydroxyl radical (∙OH), hydroperoxyl radical (HOO∙), singlet oxygen ((1)O2), and peroxyl radical (ROO∙). Two endogenous sources of reactive oxygen species are the mammalian CYP-dependent microsomal electron transport system and the mitochondrial electron transport chain.

Monooxygenase, peroxidase and peroxygenase properties and reaction mechanisms of cytochrome P450 enzymes.

This review examines the monooxygenase, peroxidase and peroxygenase properties and reaction mechanisms of cytochrome P450 (CYP) enzymes in bacterial, archaeal and mammalian systems. CYP enzymes catalyze monooxygenation reactions by inserting one oxygen atom from O2 into an enormous number and variety of substrates. The catalytic versatility of CYP stems from its ability to functionalize unactivated carbon-hydrogen (C-H) bonds of substrates through monooxygenation.

Hepatic bile acid metabolism and expression of cytochrome P450 and related enzymes are altered in Bsep (-/-) mice.

The bile salt export pump (BSEP/Bsep; gene symbol ABCB11/Abcb11) translocates bile salts across the hepatocyte canalicular membrane into bile in humans and mice. In humans, mutations in the ABCB11 gene cause a severe childhood liver disease known as progressive familial intrahepatic cholestasis type 2. Targeted inactivation of mouse Bsep produces milder persistent cholestasis due to detoxification of bile acids through hydroxylation and alternative transport pathways.

The monooxygenase, peroxidase, and peroxygenase properties of cytochrome P450.

This review examines the monooxygenase, peroxidase, and peroxygenase properties of cytochrome P450 (P450)1 enzymes and their mechanisms of action in archaeal, bacterial, and mammalian systems. In the P450 catalytic cycle, a transient iron oxo monooxygenating species is generated that reacts with substrate to produce a monooxygenated product. We describe results of early investigations that endeavored to trap and detect this elusive monooxygenating species, as well as results of experiments that attempted to generate and characterize this active oxidant spectroscopically after reacting ferric P450 enzymes with peroxy compounds (e.

2,2',3,3',6,6'-Hexachlorobiphenyl (PCB 136) is enantioselectively oxidized to hydroxylated metabolites by rat liver microsomes.

Developmental exposure to multiple ortho-substituted polychlorinated biphenyls (PCBs) causes adverse neurodevelopmental outcomes in laboratory animals and humans by mechanisms involving the sensitization of Ryanodine receptors (RyRs). In the case of PCB 136, the sensitization of RyR is enantiospecific, with only (-)-PCB 136 being active. However, the role of enantioselective metabolism in the developmental neurotoxicity of PCB 136 is poorly understood.

2,2',3,3',6,6'-Hexachlorobiphenyl (PCB 136) atropisomers interact enantioselectively with hepatic microsomal cytochrome P450 enzymes.

2,2',3,3',6,6'-Hexachlorobiphenyl (PCB 136) is a chiral and highly neurotoxic PCB congener of environmental relevance. (+)-PCB 136 was previously shown to be enriched in tissues from mice treated with racemic PCB 136. We investigated the spectral interactions of (+)-, (-)-, and (+/-)-PCB 136 with mouse and rat hepatic microsomal cytochrome P450 (P450) enzymes to test the hypothesis that enantioselective binding to specific P450 enzymes causes the enrichment of (+)-PCB 136 in vivo.

Differential inhibition of hepatic microsomal alkoxyresorufin O-dealkylation activities by tetrachlorobiphenyls.

Polychlorinated biphenyls (PCBs) elicit a spectrum of biochemical and toxic effects in exposed animals. In the present study, we assessed the effect of PCB structure, using four symmetrically-substituted PCBs, on cytochrome P450 (CYP)-mediated methoxy-, ethoxy- and benzyloxyresorufin O-dealkylase (MROD, EROD and BROD, respectively) activities. We found that 2,2',4,4'-tetrachlorobiphenyl (PCB 47), 2,2',5,5'-tetrachlorobiphenyl (PCB 52), 2,2',6,6'-tetrachlorobiphenyl (PCB 54) and 3,3',4,4'-tetrachlorobiphenyl (PCB 77) inhibited alkoxyresorufin O-dealkylase activities in hepatic microsomes from 3-methylcholanthrene (MC) or phenobarbital (PB)-treated rats.

Lipid reserve dynamics and magnification of persistent organic pollutants in spawning sockeye salmon (Oncorhynchus nerka) from the Fraser River, British Columbia.

Pacific sockeye salmon (Oncorhynchus nerka) can travel several hundred kilometers to reach native spawning grounds and fulfill semelparous reproduction. The dramatic changes in lipid reserves during upstream migration can greatly affect internal toxicokinetics of persistent organic pollutants (POPs) such as PCBs, PCDDs, and PCDFs. We measured lipid content changes and contaminant concentrations in tissues (liver, muscle, roe/gonads) and biomarker responses (ethoxyresorufin O-deethylase or EROD activity and CYP1A levels) in two Pacific sockeye salmon stocks sampled at several locations along their spawning migration in the Fraser River, British Columbia.

Spectral interactions of tetrachlorobiphenyls with hepatic microsomal cytochrome p450 enzymes.

This study investigated the spectral interactions of hepatic microsomal cytochrome p450 (CYP) enzymes with four symmetrical polychlorinated biphenyls (PCBs): 2,2',4,4'-tetrachlorobiphenyl (PCB 47); 2,2',5,5'-tetrachlorobiphenyl (PCB 52); 2,2',6,6'-tetrachlorobiphenyl (PCB 54); and 3,3',4,4'-tetrachlorobiphenyl (PCB 77). The PCBs were selected to explore structure-activity relationships and the effect of the chlorination pattern on PCB-CYP spectral interactions. To examine CYP enzyme specificity, difference spectra were measured with hepatic microsomes prepared from control, phenobarbital (PB)-, 3-methylcholanthrene (MC)-, and dexamethasone (DEX)-treated rats in the absence and presence of CYP-specific antibodies.