Pathway Map Details

Naphthalene metabolism



view in full size
| open in MetaCore

Object list (links open in MetaCore):

ACYP1, GSTA2, DNA, beta-Naphthyl phosphate, AKR1C4, 1.1.1.21, CYP2C8, 2-Naphthol, ALDX, multi-step reaction, CYP2E1, ALDR, 2.5.1.18, AKR7A2, 2.5.1.18, 1.14.14.1, 1,2-Dihydroxy-3,4-epoxy- 1,2,3,4-tetrahydronaphthalene, (1R)-Glutathionyl-(2R)-hydroxy-1,2-dihydronaphthalene, CYP1A1, (1R)-N-Acetyl-L-cysteinyl- (2R)-hydroxy-1,2 -dihydronaphthalene, 1.1.1.21, CYP2F1, spontaneous, (1R)-Hydroxy-(2R)-N-acetyl -L-cysteinyl-1,2- dihydronaphthalene, (1S)-Hydroxy-(2S)-N-acetyl- L-cysteinyl-1,2- dihydronaphthalene, (1R)-Hydroxy-(2R)-glutathionyl-1,2-dihydronaphthalene, (1R,2R)-3-[(1,2-Dihydro-2-hydroxy -1-naphthalenyl)thio]-2- oxopropanoic acid, 1.14.14.1, HYEP, 3.6.1.7, (1R,2S)-Naphthalene epoxide, 2.5.1.18, AKR1C2, 1,2-Naphthoquinone, multi-step reaction, 3.3.2.9, 1.3.1.20, 1.14.14.1, 1.14.14.1, spontaneous, Naphthalene, GSTA1, Naphthalene- 1,2-oxide, CYP1A2, GSTM1, (1S)-Hydroxy-(2S)-glutathionyl-1,2-dihydronaphthalene, 1,2-Dihydronaphthalene-1,2-diol, CYP2S1, CYP2A6, AKR1C1, 1,2-Naphthalenediol, 2-Hydroxynaph thalen-1-one, AKR1C3, CYP3A4, GSTT1, (1S,2R)-Naphthalene epoxide, GSTP1, spontaneous, 3.3.2.9, multi-step reaction, CYP2C9, 3.3.2.9, EPHX2

Description:

Naphthalene metabolism

Toxicity of Naphthalene in cell culture and animal models has to do with metabolisation of this compound by cytochrome P450 monooxygenases. Deactivation of Naphthalene involves epoxidation followed by glutathione conjugation and mercapturic acid formation [1]. Naphthalene is stereoselectively metabolized to form (1R,2S)-Naphthalene epoxide and (1S,2R)-Naphthalene epoxide in the presence of following enzymes: Cytochrome P450, family 1 subfamily A polypeptides 1 and 2 ( CYP1A1 and CYP1A2 ), Cytochrome P450, family 2, subfamily E, polypeptide 1 ( CYP2E1 ), (Cytochrome P450, family 2, subfamily F, polypeptide 1 ( CYP2F1 ), (Cytochrome P450, family 3, subfamily A, polypeptide 4 ( CYP3A4 ) and Cytochrome P450, family 2, subfamily A, polypeptide 6 ( CYP2A6 ) [2], [3], [4], [5].

In the presence of glutathione and glutathione transferases, (1R,2S)-Naphthalene epoxide and (1S,2R)-Naphthalene epoxide are metabolized to three conjugates: (1R)-Glutathionyl-(2R)-hydroxy-naphthalene, ( 1S)-Hydroxy-(2S)-glutathionyl-1,2-dihydronaphthalene and (1R)-Hydroxy-(2R)-glutathionyl-1,2-dihydronaphthalene. These reactions are catalyzed by Glutathione S-transferases A1 and A2 ( GSTA1 and GSTA2 ) [6], [7], [8], [9], [10], [11], [12], Glutathione S-transferase M1 ( GSTM1 ) [13], [14], [15], [16], Glutathione S-transferase pi 1 ( GSTP1 ) [13], [14], [15], [16] and Glutathione S-transferase theta 1 [ ( GSTT1 ) [16].

These three glutathione conjugates react with Mercapturic acid ( N-Acetyl-(L)-cysteine ) to form mercapturic acid conjugates of Naphthalene (1R)-N-Acetyl-L-cysteinyl-(2R)-hydroxy-1,2-dihydronaphthalene, (1R)-Hydroxy-(2R)-N-acetyl-L-cysteinyl-1,2-dihydronaphthalene [1] and (1S)-Hydroxy-(2S)-N-acetyl-L-cysteinyl-1,2-dihydronaphthalene [17], [1].

Epoxide hydrolases catalyze hydration of the arene oxide intermediates. One of such enzymes, Epoxide hydrolase 1, microsomal (xenobiotic) ( HYEP ), metabolizes both (1R,2S)-Naphthalene epoxide and (1S,2R)-Naphthalene epoxide to 1,2-Dihydronaphthalene-1,2-diol [18], [19], [4]. HYEP, together with Epoxide hydrolase 2, cytoplasmic ( EPHX2 ), can also catalyze formation of 1,2-Dihydronaphthalene-1,2-diol from Naphthalene-1,2-oxide [19], [20].

The oxidation of 1,2-Dihydronaphthalene-1,2-diol to 1,2-Naphthoquinone is carried out through intermediate metabolite 1,2-Naphthalenediol. This oxidation is catalyzed by the family of aldo-keto reductase enzymes that includes: aldo-keto reductase family 1, member C1 (dihydrodiol dehydrogenase 1; 20-alpha (3-alpha)-hydroxysteroid dehydrogenase) ( AKR1C1 ), Aldo-keto reductase family 1, member C3 (3-alpha hydroxysteroid dehydrogenase, type II), ( AKR1C3), Aldo-keto reductase family 1, member C2 (dihydrodiol dehydrogenase 2; bile acid binding protein; 3-alpha hydroxysteroid dehydrogenase, type III) (AKR1C2), and Aldo-keto reductase family 1, member C4 (chlordecone reductase; 3-alpha hydroxysteroid dehydrogenase, type I; dihydrodiol dehydrogenase 4) ( AKR1C4 ), Aldo-keto reductase family 1 member B1 (aldose reductase) (ALDR ), and Aldo-keto reductase family 1, member A1 (aldehyde reductase) ( ALDX ) [21], [22], [23]. 1,2-Dihydronaphthalene-1,2-diol can also be oxidized to 1,2-Dihydroxy-3,4-epoxy-1,2,3,4-tetrahydronaphthalene in the reaction catalyzed by P450cytochromes Cytochrome P450, family 2, subfamily A, polypeptide 6 ( CYP2A6 ), Cytochrome P450, family 2, subfamily F, polypeptide 1 (CYP2F1 ), Cytochrome P450, family 1, subfamily A, polypeptide 1 ( CYP1A1 ), Cytochrome P450, family 2, subfamily C, polypeptide 9 ( CYP2C9 ), Cytochrome P450, family 3, subfamily A, polypeptide 4 ( CYP3A4 ), and Cytochrome P450, family 2, subfamily C, polypeptide 8 ( CYP2C8 ) [24], [25], [4].

1,2-Naphthoquinone can be also formed through oxidation of 2-Naphthol, the latter being spontaneously formed from (1R,2S)-Naphthalene epoxide and (1S,2R)-Naphthalene epoxide [4]. Oxidation of 2-Naphthol is catalyzed by Cytochrome P450, family 2, subfamily E, polypeptide 1 ( CYP2E1 ), Cytochrome P450, family 1, subfamily A, polypeptide 2 ( CYP1A2 ), and Cytochrome P450, family 1, subfamily A, polypeptide ( CYP1A1 ) [2], [3], [4]. Beta-Naphthyl phosphate can be converted to 2-Naphthol by Acylphosphatase 1, erythrocyte (common) type ( ACYP1 ) [26], [27].

Based on the knowledge of Naphthalene metabolism, it is believed that this compound causes initiation of cancers via its activation and interaction of 1,2-Naphthoquinone with DNA to form the depurinating adducts [28]. Furthermore, 1,2-Naphthoquinone can be reversibly reduced to 2-Hydroxynaphthalen-1-one in the reaction catalyzed by Aldo-keto reductase family 7, member A2 (aflatoxin aldehyde reductase) ( AKR7A2 ), Aldo-keto reductase family 1, member A1 (aldehyde reductase) ( ALDX ) and Aldo-keto reductase family 1, member B1 (aldose reductase) ( ALDR ) [29], [30], [21], [31].

References:

  1. Marco MP, Nasiri M, Kurth MJ, Hammock BD
    Enzyme-linked immunosorbent assay for the specific detection of the mercapturic acid metabolites of naphthalene. Chemical research in toxicology 1993 May-Jun;6(3):284-93
  2. Doherty MA, Makowski R, Gibson GG, Cohen GM
    Cytochrome P-450 dependent metabolic activation of 1-naphthol to naphthoquinones and covalent binding species. Biochemical pharmacology 1985 Jul 1;34(13):2261-7
  3. Wilson AS, Davis CD, Williams DP, Buckpitt AR, Pirmohamed M, Park BK
    Characterisation of the toxic metabolite(s) of naphthalene. Toxicology 1996 Dec 18;114(3):233-42
  4. Cho TM, Rose RL, Hodgson E
    In vitro metabolism of naphthalene by human liver microsomal cytochrome P450 enzymes. Drug metabolism and disposition: the biological fate of chemicals 2006 Jan;34(1):176-83
  5. Genter MB, Marlowe J, Kevin Kerzee J, Dragin N, Puga A, Dalton TP, Nebert DW
    Naphthalene toxicity in mice and aryl hydrocarbon receptor-mediated CYPs. Biochemical and biophysical research communications 2006 Sep 15;348(1):120-3
  6. Buckpitt AR, Bahnson LS
    Naphthalene metabolism by human lung microsomal enzymes. Toxicology 1986 Nov;41(3):333-41
  7. Buckpitt A, Chang AM, Weir A, Van Winkle L, Duan X, Philpot R, Plopper C
    Relationship of cytochrome P450 activity to Clara cell cytotoxicity. IV. Metabolism of naphthalene and naphthalene oxide in microdissected airways from mice, rats, and hamsters. Molecular pharmacology 1995 Jan;47(1):74-81
  8. Plopper CG, Van Winkle LS, Fanucchi MV, Malburg SR, Nishio SJ, Chang A, Buckpitt AR
    Early events in naphthalene-induced acute Clara cell toxicity. II. Comparison of glutathione depletion and histopathology by airway location. American journal of respiratory cell and molecular biology 2001 Mar;24(3):272-81
  9. Nan HM, Kim H, Lim HS, Choi JK, Kawamoto T, Kang JW, Lee CH, Kim YD, Kwon EH
    Effects of occupation, lifestyle and genetic polymorphisms of CYP1A1, CYP2E1, GSTM1 and GSTT1 on urinary 1-hydroxypyrene and 2-naphthol concentrations. Carcinogenesis 2001 May;22(5):787-93
  10. Svensson R, Greno C, Johansson AS, Mannervik B, Morgenstern R
    Synthesis and characterization of 6-chloroacetyl-2-dimethylaminonaphthalene as a fluorogenic substrate and a mechanistic probe for glutathione transferases. Analytical biochemistry 2002 Dec 15;311(2):171-8
  11. West JA, Van Winkle LS, Morin D, Fleschner CA, Forman HJ, Plopper CG
    Repeated inhalation exposures to the bioactivated cytotoxicant naphthalene (NA) produce airway-specific Clara cell tolerance in mice. Toxicological sciences : an official journal of the Society of Toxicology 2003 Sep;75(1):161-8
  12. Phimister AJ, Lee MG, Morin D, Buckpitt AR, Plopper CG
    Glutathione depletion is a major determinant of inhaled naphthalene respiratory toxicity and naphthalene metabolism in mice. Toxicological sciences : an official journal of the Society of Toxicology 2004 Nov;82(1):268-78
  13. Van Winkle LS, Gunderson AD, Shimizu JA, Baker GL, Brown CD
    Gender differences in naphthalene metabolism and naphthalene-induced acute lung injury. American journal of physiology. Lung cellular and molecular physiology 2002 May;282(5):L1122-34
  14. Boland B, Lin CY, Morin D, Miller L, Plopper C, Buckpitt A
    Site-specific metabolism of naphthalene and 1-nitronaphthalene in dissected airways of rhesus macaques. The Journal of pharmacology and experimental therapeutics 2004 Aug;310(2):546-54
  15. Baldwin RM, Shultz MA, Buckpitt AR
    Bioactivation of the pulmonary toxicants naphthalene and 1-nitronaphthalene by rat CYP2F4. The Journal of pharmacology and experimental therapeutics 2005 Feb;312(2):857-65
  16. Shimada T
    Xenobiotic-metabolizing enzymes involved in activation and detoxification of carcinogenic polycyclic aromatic hydrocarbons. Drug metabolism and pharmacokinetics 2006 Aug;21(4):257-76
  17. Buonarati M, Jones AD, Buckpitt A
    In vivo metabolism of isomeric naphthalene oxide glutathione conjugates. Drug metabolism and disposition: the biological fate of chemicals 1990 Mar-Apr;18(2):183-9
  18. van Bladeren PJ, Vyas KP, Sayer JM, Ryan DE, Thomas PE, Levin W, Jerina DM
    Stereoselectivity of cytochrome P-450c in the formation of naphthalene and anthracene 1,2-oxides. The Journal of biological chemistry 1984 Jul 25;259(14):8966-73
  19. Wang P, Meijer J, Guengerich FP
    Purification of human liver cytosolic epoxide hydrolase and comparison to the microsomal enzyme. Biochemistry 1982 Nov 9;21(23):5769-76
  20. Tingle MD, Pirmohamed M, Templeton E, Wilson AS, Madden S, Kitteringham NR, Park BK
    An investigation of the formation of cytotoxic, genotoxic, protein-reactive and stable metabolites from naphthalene by human liver microsomes. Biochemical pharmacology 1993 Nov 2;46(9):1529-38
  21. Sugiyama K, Wang TC, Simpson JT, Rodriguez L, Kador PF, Sato S
    Aldose reductase catalyzes the oxidation of naphthalene-1, 2-dihydrodiol for the formation of ortho-naphthoquinone. Drug metabolism and disposition: the biological fate of chemicals 1999 Jan;27(1):60-7
  22. Palackal NT, Lee SH, Harvey RG, Blair IA, Penning TM
    Activation of polycyclic aromatic hydrocarbon trans-dihydrodiol proximate carcinogens by human aldo-keto reductase (AKR1C) enzymes and their functional overexpression in human lung carcinoma (A549) cells. The Journal of biological chemistry 2002 Jul 5;277(27):24799-808
  23. Jin Y, Penning TM
    Molecular docking simulations of steroid substrates into human cytosolic hydroxysteroid dehydrogenases (AKR1C1 and AKR1C2): insights into positional and stereochemical preferences. Steroids 2006 May;71(5):380-91
  24. Penning TM, Burczynski ME, Hung CF, McCoull KD, Palackal NT, Tsuruda LS
    Dihydrodiol dehydrogenases and polycyclic aromatic hydrocarbon activation: generation of reactive and redox active o-quinones. Chemical research in toxicology 1999 Jan;12(1):1-18
  25. Lanza DL, Code E, Crespi CL, Gonzalez FJ, Yost GS
    Specific dehydrogenation of 3-methylindole and epoxidation of naphthalene by recombinant human CYP2F1 expressed in lymphoblastoid cells. Drug metabolism and disposition: the biological fate of chemicals 1999 Jul;27(7):798-803
  26. Paoli P, Pazzagli L, Giannoni E, Caselli A, Manao G, Camici G, Ramponi G
    A nucleophilic catalysis step is involved in the hydrolysis of aryl phosphate monoesters by human CT acylphosphatase. The Journal of biological chemistry 2003 Jan 3;278(1):194-9
  27. Degl'Innocenti D, Marzocchini R, Malentacchi F, Ramazzotti M, Raugei G, Ramponi G
    ACYP1 gene possesses two alternative splicing forms that induce apoptosis. IUBMB life 2004 Jan;56(1):29-33
  28. Saeed M, Higginbotham S, Rogan E, Cavalieri E
    Formation of depurinating N3adenine and N7guanine adducts after reaction of 1,2-naphthoquinone or enzyme-activated 1,2-dihydroxynaphthalene with DNA Implications for the mechanism of tumor initiation by naphthalene. Chemico-biological interactions 2006 Dec 16;
  29. Bhatnagar A, Das B, Gavva SR, Cook PF, Srivastava SK
    The kinetic mechanism of human placental aldose reductase and aldehyde reductase II. Archives of biochemistry and biophysics 1988 Mar;261(2):264-74
  30. Bhatnagar A, Liu SQ, Petrash JM, Srivastava SK
    Mechanism of inhibition of aldose reductase by menadione (vitamin K3). Molecular pharmacology 1992 Nov;42(5):917-21
  31. O'connor T, Ireland LS, Harrison DJ, Hayes JD
    Major differences exist in the function and tissue-specific expression of human aflatoxin B1 aldehyde reductase and the principal human aldo-keto reductase AKR1 family members. The Biochemical journal 1999 Oct 15;343 Pt 2:487-504