Benzo[a]pyrene metabolism

Benzo[a]pyrene metabolism

Benzo[a]pyrene is a procarcinogen produced during incomplete combustion of organic compounds such as oil, gasoline and charbroiled food. The mechanism of carcinogenesis of Benzo[a]pyrene is defined by its enzymatic conversion to the ultimate mutagen, Benzo[a]pyrene diol epoxide (BPDE,). This molecule intercalates in DNA by forming covalent bond with the nucleophilic guanine nucleotide bases at the N2 position. BPDE is the carcinogenic product of three enzymatic reactions.

Benzo[a]pyrene is first oxidized by cytochromes P450 to form a variety of products, including Benzo[a]pyrene 7,8-oxide. The following cytochromes are capable of oxidizing Benzo[a]pyrene: Cytochrome P450, family 1, subfamily A, polypeptide 1 (CYP1A1) [1], [2], Cytochrome P450, family 1, 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. The ultimate carcinogen is formed after another reaction with cytochrome P450 to yield the benzopyrene 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. Conjugation of 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], UDP glucuronosyltransferase 1 family, polypeptide A7C (UGT1A7C) [13], UDP glucuronosyltransferase 1 family, polypeptide A9 (UGT1A9) [12], [13].

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