Metabolism of polycyclic compounds. 21. The metabolism of phenanthrene in rabbits and rats: dihydrodihydroxy compounds and related glucosiduronic acids

Boyland, E.; Sims, P.

doi:10.1042/bj0840571

Cited by 70 publications

(14 citation statements)

References 28 publications

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“…The absolute configuration of the fungal phenanthrene 3,4-dihydrodiol is proposed to be 3S,4S. Since trans-3,4-dihydroxy-3,4-dihydrophenanthrene is a very minor metabolite in the mammalian metabolism of phenanthrene (4,11,19), a direct comparison of the CD spectra could not be made. However, a phenanthrene trans-3,4-dihydrodiol formed from the metabolism of phenanthrene by liver microsomes from 3-methylcholanthrene-treated rats was reported to have an optical purity of 97% enriched in the R,R enantiomer (19).…”

Section: Resultsmentioning

confidence: 99%

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Stereoselective metabolism of anthracene and phenanthrene by the fungus Cunninghamella elegans

Cerniglia¹,

Yang²

1984

Appl Environ Microbiol

115

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The fungus Cunninghamella elegans oxidized anthracene and phenanthrene to form predominately transdihydrodiols. The metabolites were isolated by reversed-phase high-pressure liquid chromatography for structural and conformational analyses. Comparison of the circular dichroism spectrum of the fungal trans-1,2-dihydroxy-1,2-dihydroanthracene to that formed by rat liver microsomes indicated that the major enantiomer of the trans-1,2-dihydroxy-1,2-dihydroanthracene formed by C. elegans had an S,S absolute stereochemistry, which is opposite to the predominately 1R,2R dihydrodiol formed by rat liver microsomes. C. elegans oxidized phenanthrene primarily in the 1,2-positions to form trans-1,2-dihydroxy-1,2-dihydrophenanthrene. In addition, a minor amount of trans-3,4-dihydroxy-3,4-dihydrophenanthrene was detected. Metabolism at the K-region (9,10-positions) of phenanthrene was not detected. Comparison of the circular dichroism spectra of the phenanthrene trans-1,2and trans-3,4-dihydrodiols formed by C. elegans to those formed by mammalian enzymes indicated that each of the dihydrodiols formed by C. elegans had an S,S absolute configuration. The results indicate that there are differences in both the regio-and stereoselective metabolism of anthracene and phenanthrene between the fungus C. elegans and rat liver microsomes.

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Section: Resultsmentioning

confidence: 99%

“…Interestingly, there was no metabolism at the 9,10 positions (K-region) of phenanthrene as evidenced by the failure to detect trans-9,10-dihydroxy-9,10dihydrophenanthrene (retention time, 6.7 min). trans-9,10-Dihydroxy-9,10-dihydrophenanthrene is a major metabolite in the mammalian metabolism of phenanthrene (4,11,19).…”

Section: Resultsmentioning

confidence: 99%

Stereoselective metabolism of anthracene and phenanthrene by the fungus Cunninghamella elegans

Cerniglia¹,

Yang²

1984

Appl Environ Microbiol

115

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“…It should be mentioned that we did not determine formation of epoxide intermediates during metabolism of the above three chemicals by P450 enzymes in this study, although ther are reports to be suggested to produce epoxides of these chemicals by P450 enzymes in laboratory animals. 10, 12, 16, 20, 21 …”

Section: Discussionmentioning

confidence: 99%

Structure–Function Studies of Naphthalene, Phenanthrene, Biphenyl, and Their Derivatives in Interaction with and Oxidation by Cytochromes P450 2A13 and 2A6

Shimada

Takenaka

Kakimoto

et al. 2016

Chem. Res. Toxicol.

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Naphthalene, phenanthrene, and biphenyl and their derivatives having different ethynyl, propynyl, butynyl, and propargyl ether substitutions were examined for their interaction with and oxidation by cytochromes P450 (P450) 2A13 and 2A6. Spectral interaction studies suggested that most of these chemicals interacted with P450 2A13 to induce Type I binding spectra more readily than with P450 2A6. Among the various substituted derivatives examined, 2-ethynylnaphthalene, 2-naphthalene propargyl ether, 3-ethynylphenanthrene, and 4-biphenyl propargyl ether had larger ΔAmax/Ks values in inducing Type I binding spectra with P450 2A13 than their parent compounds. P450 2A13 was found to oxidize naphthalene, phenanthrene, and biphenyl to 1-naphthol, 9-hydroxyphenanthrene, and 2- and/or 4-hydroxybiphenyl, respectively, at much higher rates than P450 2A6. Other human P450 enzymes including P450s 1A1, 1A2, 1B1, 2C9, and 3A4 had lower rates of oxidation of naphthalene, phenanthrene, and biphenyl than P450s 2A13 and 2A6. Those alkynylated derivatives that strongly induced Type I binding spectra with P450s 2A13 and 2A6 were extensively oxidized by these enzymes upon analysis with HPLC. Molecular docking studies supported the hypothesis that ligand-interaction energies (U values) obtained with reported crystal structures of P450 2A13 and 2A6 bound to 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, indole, pilocarpine, nicotine, and coumarin are of use in understanding the basis of possible molecular interaction of these xenobiotic chemicals with active sites of P4502A13 and 2A6 enzymes. In fact, the ligand-interaction energies with P450 2A13 4EJG bound to these chemicals were found to relate to their induction of Type I binding spectra.

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“…DEP are composed of a large number of organic components, such as polycyclic aromatic hydrocarbons, nitroaromatic hydrocarbons, heterocyclics, aldehydes and quinones (Bérubé et al 1997). Among the DEP components, 9,10-phenanthrenequinone (9,10-PQ), a major quinone that is produced in biological and photo-oxidative reactions of phenanthrene (Boyland and Sims 1962;Schuetzle 1983), is extremely harmful and is known to induce apoptotic cell death at submicromolar concentrations (Matsunaga et al 2008). This 9,10-PQinduced cellular apoptosis is mainly attributed to the generation of reactive oxygen species (ROS) and subsequent ROSdependent pathways, which resemble the toxic mechanisms of DEP (Kumagai et al 1997).…”

Section: Introductionmentioning

confidence: 99%

9,10-Phenanthrenequinone promotes secretion of pulmonary aldo-keto reductases with surfactant

et al. 2012

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9,10-Phenanthrenequinone (9,10-PQ), a major quinone in diesel exhaust particles, induces apoptosis via the generation of reactive oxygen species (ROS) because of 9,10-PQ redox cycling. We have found that intratracheal infusion of 9,10-PQ facilitates the secretion of surfactant into rat alveolus. In the cultured rat lung, treatment with 9,10-PQ results in an increase in a lower-density surfactant by ROS generation through redox cycling of the quinone. The surfactant contains aldo-keto reductase (AKR) 1C15, which reduces 9,10-PQ and the enzyme level in the surfactant increases on treatment with 9,10-PQ suggesting an involvement of AKR1C15 in the redox cycling of the quinone. In six human cell types (A549, MKN45, Caco2, Hela, Molt4 and U937) only type II epithelial A549 cells secrete three human AKR1C subfamily members (AKR1C1, AKR1C2 and AKR1C3) with the surfactant into the medium; this secretion is highly increased by 9,10-PQ treatment. Using in vitro enzyme inhibition analysis, we have identified AKR1C3 as the most abundantly secreted AKR1C member. The AKR1C enzymes in the medium efficiently reduce 9,10-PQ and initiate its redox cycling accompanied by ROS production. The exposure of A549 cells to 9,10-PQ provokes viability loss, which is significantly protected by the addition of the AKR1C3 inhibitor and antioxidant enzyme and by the removal of the surfactants from the culture medium. Thus, the AKR1C enzymes secreted in pulmonary surfactants probably participate in the toxic mechanism triggered by 9,10-PQ.

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Metabolism of polycyclic compounds. 21. The metabolism of phenanthrene in rabbits and rats: dihydrodihydroxy compounds and related glucosiduronic acids

Cited by 70 publications

References 28 publications

Stereoselective metabolism of anthracene and phenanthrene by the fungus Cunninghamella elegans

Stereoselective metabolism of anthracene and phenanthrene by the fungus Cunninghamella elegans

Structure–Function Studies of Naphthalene, Phenanthrene, Biphenyl, and Their Derivatives in Interaction with and Oxidation by Cytochromes P450 2A13 and 2A6

9,10-Phenanthrenequinone promotes secretion of pulmonary aldo-keto reductases with surfactant

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