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2-Naphthylamine and 2-Nitronaphtalene metabolism



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SULT1A2, HYEP, CYP2F1, 2-Hydroxyaminonaphthalene, DNA, GSTA2, GSTA3, 2.5.1.18, UGT1A9, spontaneous, 3.3.2.9, 2.5.1.18, Nitro reduction, CYP1A1, 2.5.1.18, UGT1A1, CYP3A4, CYP2E1, 3.3.2.9, N-Hydroxy-2-naphthyl-sulfamic acid, 2-Amino-1-naphthylsulfate, 2-Nitro-5-glutathionyl-6-hydroxy-5,6-dihydronaphthalene, spontaneous, 2-Naphthylamine, 2.8.2.1 , SULT1A3, 2-Nitronaphthalene, 2-Amino-1-Naphthol, CYP2B1, SULT1A1, 2-Hydroxyaminonaphthalene-N-beta-D-glucuronoside, GSTA1, 2.4.1.17, 2.5.1.18, CYP1A2, Izomerization spontaneous, 2-Nitro-5,6-dihydroxy-dihydronaphthalene, 2-Nitronaphthalene-7,8-oxide, 1.14.14.1, GSTA4, UGT1A8, 2-Nitrosonaphthalene, 2-Nitro-5-hydroxy-6-glutathionyl-5,6-dihydronaphthalene, 2-Nitro-7,8-dihydroxy-dihydronaphthalene, N-oxidation, 2-Nitronaphthalene-5,6-oxide, UGT1A6, 2-Nitro-7-glutathionyl-8-hydroxy-7,8-dihydronaphthalene, 2-Hydroxyaminonaphthalene-O-beta-D-glucuronoside, UGT1A4, 1.14.14.1, GSTA5, RNA, 2.4.1.17, 2-Naphthylamine-N-beta-D-glucuronoside, 2.4.1.17, SULT1A4, UGT1A3, 2-Nitro-7-hydroxy-8-glutathionyl-7,8-dihydronaphthalene, 2.8.2.1

Description:

Naphthylamine and 2-Nitronaphtalene metabolism

Metabolism and binding studies with 2-Naphthylamine and many other arylamines have shown cytochrome P-450 catalysed N-hydroxylation to be a critical step in the activation of these compounds. Followed by glucuronidation and excretion of the glucuronides via the kidney, this reaction can account for the ability of 2-Naphthylamine to initiate tumours of the bladder [1].

2-Hydroxyamino-naphthalene is formed in the reaction of N-oxidation catalyzed by unspecific monooxygenase [2]. This compound, can spontaneous bind to DNA to form mutagenic DNA adducts. 2-Naphthylamine and 2-Hydroxyamino-naphthalene conjugate with UDP-D-glucuronic acid and form respectively 2-Naphthylamine-N-beta-D-glucuronoside and 2-Hydroxyamino-naphthalene-N-beta-D-glucuronoside. Both reactions are catalyzed by the family of glucuronosyltransferase enzymes that includes: UDP Glucuronosyltransferase 1 family, polypeptide A4 ( UGT1A4 ), UDP Glucuronosyltransferase 1 family, polypeptide A1 ( UGT1A1 ), UDP Glucuronosyltransferase 1 family, polypeptide A3 ( UGT1A3 ); UDP Glucuronosyltransferase 1 family, polypeptide A9 ( UGT1A9 ); (UDP Glucuronosyltransferase 1 family, polypeptide A8 ( UGT1A8 ), and UDP Glucuronosyltransferase 1 family, polypeptide A6 ( UGT1A6 ) [3], [2], [4], [5]. 2-Hydroxyamino-naphthalene can spontaneously isomerize further into the 2-Amino-1-naphthol. The latter conjugates with UDP-D-glucuronic acid in the reaction catalyzed by the same glucuronosyltransferase enzymes.

In addition, both 2-Hydroxyamino-naphthalene and 2-Amino-1-Naphthol form sulphate conjugates N-Hydroxy-2-naphthyl-sulfamic acid and 2-Amino-1-naphthylsulfate, respectively. Both reactions are catalyzed by the family of sulfotransferase enzymes: Sulfotransferase family, cytosolic, 1A, phenol-preferring, members 1, 2, 3 and 4 ( SULT1A1, SULT1A2, SULT1A3 and SULT1A4 ) correspondingly [2], [6], [7], [8]. Further N-Hydroxy-2-naphthyl-sulfamic acid isomerizes into 2-Amino-1-naphthylsulfate.

2-Hydroxyamino-naphthalene is formed by reduction of 2-Nitrosonaphthalene in the reaction of catalyzed by unknown oxidoreductase [9]. 2-Nitrosonaphthalene is formed by reduction of 2-Nitronaphthalene also catalyzed by unknown oxidoreductase [9].

2-Nitronaphthalene is oxidized to 2-Nitronaphthalene-5,6-oxide and 2-Nitronaphthalene-7,8-oxide by following enzymes: Cytochrome P450, family 3, subfamily A, polypeptide 4 ( CYP3A4 ), Cytochrome P450, family 1, subfamily A, polypeptide 1 ( CYP1A1 ), Cytochrome P450, family 2, subfamily E, polypeptide 1 ( CYP2E1 ), Cytochrome P450, family 1, subfamily A, polypeptide 2 ( CYP1A2 ), Cytochrome P450, family 2, subfamily F, polypeptide 1 ( CYP2F1 ) and Cytochrome P450, family 2, subfamily B ( CYP2B1 ) [10], [11], [12], [13], [14].

Epoxide hydrolase 1, microsomal (xenobiotic) ( HYEP ) hydrolyzes both 2-Nitronaphthalene-5,6-oxide and 2-Nitronaphthalene-7,8-oxide to 2-Nitro-5,6-dihydroxy-dihydronaphthalene and 2-Nitro-7,8-dihydroxy-dihydronaphthalene, respectively [15], [16], [17], [13].

Glutathione S-transferases can transfer glutathione to two positions on 2-Nitronaphthalene-5,6-oxide and 2-Nitronaphthalene-7,8-oxide molecules to form 2 -Nitro-5-glutathionyl-6-hydroxy-5,6-dihydronaphthalene, 2-Nitro-5-hydroxy-6-glutathionyl-5,6-dihydronaphthalene and 2-Nitro-7-glutathionyl-8-hydroxy-7,8-dihydronaphthalene, 2-Nitro-7-hydroxy-8-glutathionyl-7,8-dihydronaphthalene, respectively. The enzymes capable of catalyzing these reactions include: glutathione S-transferase A1, A2, A3, A4, A5 ( GSTA1, GSTA2, GSTA3, GSTA4 and GSTA5 ) accordingly [18], [19], [20], [21], [22].

References:

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    Metabolism of 2-naphthylamine and benzidine by rat and human bladder organ cultures. Carcinogenesis 1984 Jul;5(7):949-54
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    Alteration of urinary levels of the carcinogen, N-hydroxy-2-naphthylamine, and its N-glucuronide in the rat by control of urinary pH, inhibition of metabolic sulfation, and changes in biliary excretion. Chemico-biological interactions 1981 Jan;33(2-3):129-47
  3. Kadlubar FF, Miller JA, Miller EC
    Hepatic microsomal N-glucuronidation and nucleic acid binding of N-hydroxy arylamines in relation to urinary bladder carcinogenesis. Cancer research 1977 Mar;37(3):805-14
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    Glucuronidation of 1-naphthol in nuclear and microsomal fractions of the human intestine. Pharmacology 1986;33(2):103-9
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    Human UDP-glucuronosyltransferases: metabolism, expression, and disease. Annual review of pharmacology and toxicology 2000;40:581-616
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    Phenotype-genotype relationships of SULT1A1 in human liver and variations in the IC50 of the SULT1A1 inhibitor quercetin. International journal of clinical pharmacology and therapeutics 2004 Oct;42(10):561-7
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  8. Bradley ME, Benner SA
    Phylogenomic approaches to common problems encountered in the analysis of low copy repeats: the sulfotransferase 1A gene family example. BMC evolutionary biology 2005 Mar 7;5(1):22
  9. Poirier LA, Weisburger JH
    Enzymic reduction of carcinogenic aromatic nitro compounds by rat and mouse liver fractions. Biochemical pharmacology 1974 Feb 1;23(3):661-9
  10. Verschoyle RD, Carthew P, Wolf CR, Dinsdale D
    1-Nitronaphthalene toxicity in rat lung and liver: effects of inhibiting and inducing cytochrome P450 activity. Toxicology and applied pharmacology 1993 Oct;122(2):208-13
  11. 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
  12. Takemoto K, Yamazaki H, Tanaka Y, Nakajima M, Yokoi T
    Catalytic activities of cytochrome P450 enzymes and UDP-glucuronosyltransferases involved in drug metabolism in rat everted sacs and intestinal microsomes. Xenobiotica; the fate of foreign compounds in biological systems 2003 Jan;33(1):43-55
  13. 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
  14. 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
  15. 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
  16. Kitteringham NR, Davis C, Howard N, Pirmohamed M, Park BK
    Interindividual and interspecies variation in hepatic microsomal epoxide hydrolase activity: studies with cis-stilbene oxide, carbamazepine 10, 11-epoxide and naphthalene. The Journal of pharmacology and experimental therapeutics 1996 Sep;278(3):1018-27
  17. Morisseau C, Hammock BD
    Epoxide hydrolases: mechanisms, inhibitor designs, and biological roles. Annual review of pharmacology and toxicology 2005;45:311-33
  18. Prabhu KS, Reddy PV, Gumpricht E, Hildenbrandt GR, Scholz RW, Sordillo LM, Reddy CC
    Microsomal glutathione S-transferase A1-1 with glutathione peroxidase activity from sheep liver: molecular cloning, expression and characterization. The Biochemical journal 2001 Dec 1;360(Pt 2):345-54
  19. Raza H, Robin MA, Fang JK, Avadhani NG
    Multiple isoforms of mitochondrial glutathione S-transferases and their differential induction under oxidative stress. The Biochemical journal 2002 Aug 15;366(Pt 1):45-55
  20. Hayeshi R, Mukanganyama S, Hazra B, Abegaz B, Hasler J
    The interaction of selected natural products with human recombinant glutathione transferases. Phytotherapy research : PTR 2004 Nov;18(11):877-83
  21. Urbanek H, Majorowicz H, Zalewski M, Saniewski M
    Induction of glutathione S-transferase and glutathione by toxic compounds and elicitors in reed canary grass. Biotechnology letters 2005 Jul;27(13):911-4
  22. Lin CY, Boland BC, Lee YJ, Salemi MR, Morin D, Miller LA, Plopper CG, Buckpitt AR
    Identification of proteins adducted by reactive metabolites of naphthalene and 1-nitronaphthalene in dissected airways of rhesus macaques. Proteomics 2006 Feb;6(3):972-82