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 .
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) , , , .
In the presence of glutathione and glutathione transferases,
(1R,2S)-Naphthalene epoxide and
(1S,2R)-Naphthalene epoxide are metabolized to three
reactions are catalyzed by Glutathione S-transferases A1 and A2
(GSTA1 and GSTA2) , , , , , , ,
Glutathione S-transferase M1 (GSTM1) , , , , Glutathione
S-transferase pi 1 (GSTP1) , , ,  and Glutathione S-transferase theta 1 [
These three glutathione conjugates react with Mercapturic acid
(N-Acetyl-(L)-cysteine) to form mercapturic acid conjugates
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 , , . HYEP, together with Epoxide
hydrolase 2, cytoplasmic (EPHX2), can also catalyze
formation of 1,2-Dihydronaphthalene-1,2-diol from
Naphthalene-1,2-oxide , .
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) , , . 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) , , .
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
. 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) , , . Beta-Naphthyl phosphate
can be converted to 2-Naphthol by
Acylphosphatase 1, erythrocyte (common) type
(ACYP1) , .
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 . 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) , , , .
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