2-Naphthylamine and 2-Nitronaphtalene metabolism

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) [2], [3], [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 [13], [15], [16], [17].

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].

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