Fluorobenzo[a]pyrenes as probes of the mechanism of cytochrome P450-catalyzed oxygen transfer in aromatic oxygenations

Mulder, Patrick P.J.; Devanesan, Prabu; Alem, Kaj van; Lodder, Gerrit; Rogan, Eleanor G.; Cavalieri, Ercole L.

doi:10.1016/s0891-5849(02)01374-6

Cited by 10 publications

(11 citation statements)

References 32 publications

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“…These reactive oxygen species (ROS) or oxyradicals react with DNA, proteins and membrane lipids in the intracellular milieu (Nebert et al, 2000;Zangar et al, 2004). Further, dihydrodiol dehydrogenase (Bolton et al, 2000) and peroxidases (Mulder et al, 2003) were reported to be involved in the metabolic conversion of B(a)P to reactive and redox active o-quinones, that have been demonstrated in chemical systems to undergo one electron redox cycling with their semiquinone radicals resulting in the formation of ROS such as superoxide anion, H 2 O 2 and hydroxyl radicals by Fenton chemistry. Several laboratories have hypothesized that many of the cellular effects of B(a)P may be attributed to its metabolism to B(a)P quinones and their subsequent ability to generate intracellular ROS and lipid peroxidation (Lemiere et al, 2005;Casetta et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Benzo(a)pyrene‐induced acute neurotoxicity in the F‐344 rat: role of oxidative stress

Saunders

Das

Ramesh

et al. 2006

J of Applied Toxicology

152

125

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Given the link between neurotoxicity and exposure to pollutants, the potential behavioral neurotoxicity of benzo(a)pyrene [B(a)P] was investigated. Studies have established that B(a)P requires metabolic activation to highly reactive species to elicit many of its adverse effects. This study investigated the perturbation of nervous system function by correlating behavioral changes with the metabolism of B(a)P, antioxidant enzyme levels and lipid peroxidation in selected brain regions. The neurobehavioral effects of single oral doses of B(a)P (25-200 mg kg(-1) body weight) on motor activity were examined in male F-344 rats at 2, 4, 6, 12, 24, 48, 72 and 96 h post treatment. Parent B(a)P and metabolites were measured at the above mentioned time points by reverse phase HPLC. The activity of several antioxidant enzymes (superoxide dismutase, catalase and glutathione peroxidase) and levels of malondialdehyde were determined at 6 and 96 h in both the striatum and hippocampus of B(a)P exposed rats. Suppression of motor activity (up to 70%) reached a maximum at 6 h, but was reversible at 96 h in all dose groups. The kinetics of disposition data show a strong link between B(a)P metabolism and the onset and duration of behavioral effects. Benzo(a)pyrene caused a 15-70% inhibition in the activity of superoxide dismutase and glutathione peroxidase and an enhancement in catalase and lipid peroxidation (up to 68%) in the striatum and hippocampus at 6 and 96 h post treatment, respectively. These findings suggest that B(a)P-induced acute neurobehavioral toxicity may occur through oxidative stress due to inhibition of the brain antioxidant scavenging system.

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Section: Discussionmentioning

confidence: 99%

Benzo(a)pyrene‐induced acute neurotoxicity in the F‐344 rat: role of oxidative stress

Saunders

Das

Ramesh

et al. 2006

J of Applied Toxicology

152

125

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“…These experiments are corroborated by molecular orbital calculations in BP (Loew, et al, 1978; Shipman, 1978) and BP +. (Cavalieri et al, 1993; Mulder et al, 2003). The overall data suggest that electrophilic and nucleophilic substitution in BP and BP +.…”

Section: Cytochrome P450mentioning

confidence: 98%

“…, respectively, should occur most easily at C-6, C-1 and C-3, in decreasing order. Furthermore, calculation of the bond orders of BP, 6-FBP, 1-FBP and 3-FBP display the highest electron density in the 4,5- double bond, followed by the 11,12-, 9,10- and 7,8- double bond (Cavalieri et al, 1993; Mulder et al, 2003). …”

Section: Cytochrome P450mentioning

confidence: 99%

“…Fluorination of BP at C-6, C-1 and C-3 generated excellent probes for determining the mechanism by which the oxygen activated by cytochrome P450 is transferred from the enzyme to the substrate (Cavalieri et al, 1988b; Mulder et al, 2003). Combined studies of the chemistry of BP and 6-FBP, as well as the metabolism and molecular orbital calculations of BP, 6-FBP, 1-FBP and 3-FBP, enabled us to determine the mechanism of oxygen transfer by cytochrome P450 to BP to form 6-OHBP, 3-OHBP and 1-OHBP (Cavalieri et al, 1988b; Cremonesi et al, 1989; Mulder et al, 2003).…”

Section: Cytochrome P450mentioning

confidence: 99%

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The molecular etiology and prevention of estrogen-initiated cancers

Cavalieri

Rogan

2014

Molecular Aspects of Medicine

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“…The mechanism of PAH oxidation by cytochrome P450 (CYP) mono-oxygenase is complex and can involve an odd electron abstraction rebound mechanism as well as a one-electron radical cation mechanism Guengerich, 2001;Cavalieri & Rogan, 2002;Mulder et al, 2003).…”

Section: (F) Metabolismmentioning

confidence: 99%

Integrating Field Analyses with Laboratory Exposures to Assess Ecosystems Health

Hellou¹,

Beach²,

Leonard³

et al. 2012

Polycyclic Aromatic Compounds

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Fluorobenzo[a]pyrenes as probes of the mechanism of cytochrome P450-catalyzed oxygen transfer in aromatic oxygenations

Cited by 10 publications

References 32 publications

Benzo(a)pyrene‐induced acute neurotoxicity in the F‐344 rat: role of oxidative stress

Benzo(a)pyrene‐induced acute neurotoxicity in the F‐344 rat: role of oxidative stress

The molecular etiology and prevention of estrogen-initiated cancers

Integrating Field Analyses with Laboratory Exposures to Assess Ecosystems Health

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