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Naphthalene metabolism


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Naphthalene metabolism

Naphthalene metabolism

Toxicity of Naphthalene in cell culture and animal models has to do withmetabolisation of this compound by cytochrome P450 monooxygenases. Deactivation ofNaphthalene involves epoxidation followed by glutathione conjugation andmercapturic acid formation [1]. Naphthalene is stereoselectivelymetabolized to form (1R,2S)-Naphthalene epoxide and (1S,2R)-Naphthaleneepoxide in the presence of following enzymes: Cytochrome P450, family 1 subfamily Apolypeptides 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)-Naphthaleneepoxide 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 arecatalyzed 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], GlutathioneS-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 suchenzymes, Epoxide hydrolase 1, microsomal (xenobiotic) ( HYEP ), metabolizes both(1R,2S)-Naphthalene epoxide and (1S,2R)-Naphthalene epoxide to1,2-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 fromNaphthalene-1,2-oxide [19], [20].

The oxidation of 1,2-Dihydronaphthalene-1,2-diol to 1,2-Naphthoquinoneis carried out through intermediate metabolite 1,2-Naphthalenediol. Thisoxidation 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-ketoreductase family 1, member C2 (dihydrodiol dehydrogenase 2; bile acid binding protein;3-alpha hydroxysteroid dehydrogenase, type III) (AKR1C2), and Aldo-keto reductasefamily 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 (aldehydereductase) ( ALDX ) [21], [22], [23].1,2-Dihydronaphthalene-1,2-diol can also be oxidized to1,2-Dihydroxy-3,4-epoxy-1,2,3,4-tetrahydronaphthalene in the reaction catalyzed byP450cytochromes  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, polypeptide8 ( 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 iscatalyzed by Cytochrome P450, family 2, subfamily E, polypeptide 1 ( CYP2E1 ),Cytochrome P450, family 1, subfamily A, polypeptide 2 ( CYP1A2 ), and CytochromeP450, family 1, subfamily A, polypeptide ( CYP1A1 ) [2], [3], [4]. Beta-Naphthyl phosphate can be converted to2-Naphthol by Acylphosphatase 1, erythrocyte (common) type ( ACYP1 ) [26], [27].

Based on the knowledge of Naphthalene metabolism, it is believed that thiscompound causes initiation of cancers via its activation and interaction of1,2-Naphthoquinone with DNA to form the depurinating adducts [28].Furthermore, 1,2-Naphthoquinone can be reversibly reduced to2-Hydroxynaphthalen-1-one in the reaction catalyzed by Aldo-keto reductase family7, member A2 (aflatoxin aldehyde reductase) ( AKR7A2 ), Aldo-keto reductase family1, member A1 (aldehyde reductase) ( ALDX ) and Aldo-keto reductase family 1,member B1 (aldose reductase) ( ALDR ) [29],[30],[21], [31].