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2-Naphthylamine and 2-Nitronaphtalene metabolism


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2-Naphthylamine and 2-Nitronaphtalene metabolism

Naphthylamine and 2-Nitronaphtalene metabolism

Metabolism and binding studies with 2-Naphthylamine and many other arylamineshave shown cytochrome P-450 catalysed N-hydroxylation to be a critical step in theactivation of these compounds. Followed by glucuronidation and excretion of theglucuronides via the kidney, this reaction can account for the ability of2-Naphthylamine to initiate tumours of the bladder [1].

2-Hydroxyamino-naphthalene is formed in the reaction of N-oxidation catalyzedby unspecific monooxygenase [2]. This compound, can spontaneous bind to DNAto form mutagenic DNA adducts. 2-Naphthylamine and2-Hydroxyamino-naphthalene conjugate with UDP-D-glucuronic acid and formrespectively 2-Naphthylamine-N-beta-D-glucuronoside and2-Hydroxyamino-naphthalene-N-beta-D-glucuronoside. Both reactions are catalyzedby the family of glucuronosyltransferase enzymes that includes: UDPGlucuronosyltransferase 1 family, polypeptide A4 ( UGT1A4 ), UDPGlucuronosyltransferase 1 family, polypeptide A1 ( UGT1A1 ), UDPGlucuronosyltransferase 1 family, polypeptide A3 ( UGT1A3 ); UDPGlucuronosyltransferase 1 family, polypeptide A9 ( UGT1A9 ); (UDPGlucuronosyltransferase 1 family, polypeptide A8 ( UGT1A8 ), and UDPGlucuronosyltransferase 1 family, polypeptide A6 ( UGT1A6 ) [3], [2], [4], [5]. 2-Hydroxyamino-naphthalene canspontaneously isomerize further into the 2-Amino-1-naphthol. The latterconjugates with UDP-D-glucuronic acid in the reaction catalyzed by the sameglucuronosyltransferase enzymes.

In addition, both 2-Hydroxyamino-naphthalene and 2-Amino-1-Naphthol formsulphate conjugates N-Hydroxy-2-naphthyl-sulfamic acid and2-Amino-1-naphthylsulfate, respectively. Both reactions are catalyzed by thefamily 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 acidisomerizes into 2-Amino-1-naphthylsulfate.

2-Hydroxyamino-naphthalene is formed by reduction of2-Nitrosonaphthalene in the reaction of catalyzed by unknown oxidoreductase [9]. 2-Nitrosonaphthalene is formed by reduction of 2-Nitronaphthalenealso catalyzed by unknown oxidoreductase [9].

2-Nitronaphthalene is oxidized to 2-Nitronaphthalene-5,6-oxide and2-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 CytochromeP450, family 2, subfamily B ( CYP2B1 ) [10], [11], [12], [13], [14].

Epoxide hydrolase 1, microsomal (xenobiotic) ( HYEP ) hydrolyzes both2-Nitronaphthalene-5,6-oxide and 2-Nitronaphthalene-7,8-oxide to2-Nitro-5,6-dihydroxy-dihydronaphthalene and2-Nitro-7,8-dihydroxy-dihydronaphthalene, respectively [15], [16], [17], [13].

Glutathione S-transferases can transfer glutathione to two positions on2-Nitronaphthalene-5,6-oxide and 2-Nitronaphthalene-7,8-oxide molecules toform 2 -Nitro-5-glutathionyl-6-hydroxy-5,6-dihydronaphthalene,2-Nitro-5-hydroxy-6-glutathionyl-5,6-dihydronaphthalene and2-Nitro-7-glutathionyl-8-hydroxy-7,8-dihydronaphthalene,2-Nitro-7-hydroxy-8-glutathionyl-7,8-dihydronaphthalene, respectively. Theenzymes 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].