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Naphthalene metabolism
Naphthalene metabolism

Object List (links open in MetaCore):

ACYP1, GSTA2, DNA, beta-Naphthyl phosphate, AKR1C4, 1.1.1.21, CYP2C8, 2-Naphthol, ALDX, multi-step reaction, CYP2E1, ALDR, 2.5.1.18, AKR7A2, 2.5.1.18, 1.14.14.1, 1,2-Dihydroxy-3,4-epoxy- 1,2,3,4-tetrahydronaphthalene, (1R)-Glutathionyl-(2R)-hydroxy-1,2-dihydronaphthalene, CYP1A1, (1R)-N-Acetyl-L-cysteinyl- (2R)-hydroxy-1,2 -dihydronaphthalene, 1.1.1.21, CYP2F1, spontaneous, (1R)-Hydroxy-(2R)-N-acetyl -L-cysteinyl-1,2- dihydronaphthalene, (1S)-Hydroxy-(2S)-N-acetyl- L-cysteinyl-1,2- dihydronaphthalene, (1R)-Hydroxy-(2R)-glutathionyl-1,2-dihydronaphthalene, (1R,2R)-3-[(1,2-Dihydro-2-hydroxy -1-naphthalenyl)thio]-2- oxopropanoic acid, 1.14.14.1, HYEP, 3.6.1.7, (1R,2S)-Naphthalene epoxide, 2.5.1.18, AKR1C2, 1,2-Naphthoquinone, multi-step reaction, 3.3.2.9, 1.3.1.20, 1.14.14.1, 1.14.14.1, spontaneous, Naphthalene, GSTA1, Naphthalene- 1,2-oxide, CYP1A2, GSTM1, (1S)-Hydroxy-(2S)-glutathionyl-1,2-dihydronaphthalene, 1,2-Dihydronaphthalene-1,2-diol, CYP2S1, CYP2A6, AKR1C1, 1,2-Naphthalenediol, 2-Hydroxynaph thalen-1-one, AKR1C3, CYP3A4, GSTT1, (1S,2R)-Naphthalene epoxide, GSTP1, spontaneous, 3.3.2.9, multi-step reaction, CYP2C9, 3.3.2.9, EPHX2

Description

Naphthalene metabolism

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 [1]. 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 ) [2], [3], [4], [5].

In the presence of glutathione and glutathione transferases, (1R,2S)-Naphthalene epoxide and (1S,2R)-Naphthalene epoxide are metabolized to three conjugates: (1R)-Glutathionyl-(2R)-hydroxy-naphthalene, ( 1S)-Hydroxy-(2S)-glutathionyl-1,2-dihydronaphthalene and (1R)-Hydroxy-(2R)-glutathionyl-1,2-dihydronaphthalene. These reactions are catalyzed by Glutathione S-transferases A1 and A2 ( GSTA1 and GSTA2 ) [6], [7], [8], [9], [10], [11], [12], Glutathione S-transferase M1 ( GSTM1 ) [13], [14], [15], [16], Glutathione S-transferase pi 1 ( GSTP1 ) [13], [14], [15], [16] and Glutathione S-transferase theta 1 [ ( GSTT1 ) [16].

These three glutathione conjugates react with Mercapturic acid ( N-Acetyl-(L)-cysteine ) to form mercapturic acid conjugates of Naphthalene (1R)-N-Acetyl-L-cysteinyl-(2R)-hydroxy-1,2-dihydronaphthalene, (1R)-Hydroxy-(2R)-N-acetyl-L-cysteinyl-1,2-dihydronaphthalene [1] and (1S)-Hydroxy-(2S)-N-acetyl-L-cysteinyl-1,2-dihydronaphthalene [17], [1].

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 [18], [19], [4]. HYEP, together with Epoxide hydrolase 2, cytoplasmic ( EPHX2 ), can also catalyze formation of 1,2-Dihydronaphthalene-1,2-diol from Naphthalene-1,2-oxide [19], [20].

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 ) [21], [22], [23]. 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 ) [24], [25], [4].

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 [4]. 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 ) [2], [3], [4]. Beta-Naphthyl phosphate can be converted to 2-Naphthol by Acylphosphatase 1, erythrocyte (common) type ( ACYP1 ) [26], [27].

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 [28]. 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 ) [29], [30], [21], [31].

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