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 .
2-Hydroxyamino-naphthalene is formed in the reaction of
N-oxidation catalyzed by unspecific monooxygenase . 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
reactions are catalyzed by the family of glucuronosyltransferase enzymes that includes:
UDP Glucuronosyltransferase 1 family, polypeptide A4
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-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
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 , , , . Further N-Hydroxy-2-naphthyl-sulfamic
acid isomerizes into
2-Hydroxyamino-naphthalene is formed by reduction of
2-Nitrosonaphthalene in the reaction of catalyzed by unknown
oxidoreductase . 2-Nitrosonaphthalene is
formed by reduction of 2-Nitronaphthalene also catalyzed by
unknown oxidoreductase .
2-Nitronaphthalene is oxidized to
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) , , , , .
Epoxide hydrolase 1, microsomal (xenobiotic) (HYEP)
hydrolyzes both 2-Nitronaphthalene-5,6-oxide and
, , , .
Glutathione S-transferases can transfer glutathione to two positions on
2-Nitronaphthalene-7,8-oxide molecules to form
respectively. The enzymes capable of catalyzing these reactions include: glutathione
S-transferase A1, A2, A3, A4, A5 (GSTA1,
GSTA4 and GSTA5) accordingly
, , , , .
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