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Organism specific object

Benzo[a]pyrene metabolism


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Benzo[a]pyrene metabolism

Benzo[a]pyrene metabolism

Benzo[a]pyrene is a procarcinogen produced during incomplete combustion oforganic compounds such as oil, gasoline and charbroiled food. The mechanism ofcarcinogenesis of Benzo[a]pyrene is defined by its enzymatic conversion to theultimate mutagen, Benzo[a]pyrene diol epoxide ( BPDE,). This moleculeintercalates in DNA by forming covalent bond with the nucleophilic guanine nucleotidebases at the N2 position. BPDE is the carcinogenic product of three enzymaticreactions.

Benzo[a]pyrene is first oxidized by cytochromes P450 to form a variety ofproducts, including Benzo[a]pyrene 7,8-oxide. The following cytochromes arecapable of oxidizing Benzo[a]pyrene: Cytochrome P450, family 1, subfamily A,polypeptide 1 (CYP1A1) [1], [2], Cytochrome P450, family1, subfamily A, polypeptide 2 ( CYP1A2) [2], [3],Cytochrome P450, family 1, subfamily B, polypeptide 1 ( CYP1B1 ) [3],Cytochrome P450, family 2, subfamily C, polypeptide 18 ( CYP2C18 ) [4], Cytochrome P450, family 2, subfamily C, polypeptide 8 ( CYP2C8 ) [5], Cytochrome P450, family 2, subfamily C, polypeptide 9 ( CYP2C9 ) [2], and Cytochrome P450, family 3, subfamily A, polypeptide 4 ( CYP3A4 )[1]. Benzo[a]pyrene 7,8-oxide is metabolized by Epoxide hydrolase 1,microsomal (xenobiotic) ( HYEP ) [6], [7], [8] that opens the epoxide ring to produce Benzo[a]pyrene-7,8-diol. Theultimate carcinogen is formed after another reaction with cytochrome P450 to yield thebenzopyrene diol epoxide.

The reactive species formed from Benzo[a]pyrene, namely Benzo[a]pyrene-4,5- 7,8-9,10- epoxides and others, are substrates for the conjugation reactions. Conjugationof Benzo[a]pyrene derivatives is catalyzed by Glutathione S-transferase pi 1 (GSTP1 ) [9], [10], UDP glucuronosyltransferase 1 family,polypeptide A10 ( UGT1A10) [11], UDP glucuronosyltransferase 1 family,polypeptide A6 ( UGT1A6 ) [12], [13], UDPglucuronosyltransferase 1 family, polypeptide A7C ( UGT1A7C) [13], UDPglucuronosyltransferase 1 family, polypeptide A9 ( UGT1A9 ) [13],[12].