Benzo[a]pyrene metabolism

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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].

References:

  1. Yun CH, Shimada T, Guengerich FP
    Roles of human liver cytochrome P4502C and 3A enzymes in the 3-hydroxylation of benzo(a)pyrene. Cancer research 1992 Apr 1;52(7):1868-74
  2. Bauer E, Guo Z, Ueng YF, Bell LC, Zeldin D, Guengerich FP
    Oxidation of benzo[a]pyrene by recombinant human cytochrome P450 enzymes. Chemical research in toxicology 1995 Jan-Feb;8(1):136-42
  3. Guo Z, Gillam EM, Ohmori S, Tukey RH, Guengerich FP
    Expression of modified human cytochrome P450 1A1 in Escherichia coli: effects of 5' substitution, stabilization, purification, spectral characterization, and catalytic properties. Archives of biochemistry and biophysics 1994 Aug 1;312(2):436-46
  4. Gautier JC, Lecoeur S, Cosme J, Perret A, Urban P, Beaune P, Pompon D
    Contribution of human cytochrome P450 to benzo[a]pyrene and benzo[a]pyrene-7,8-dihydrodiol metabolism, as predicted from heterologous expression in yeast. Pharmacogenetics 1996 Dec;6(6):489-99
  5. Shimada T, Gillam EM, Sutter TR, Strickland PT, Guengerich FP, Yamazaki H
    Oxidation of xenobiotics by recombinant human cytochrome P450 1B1. Drug metabolism and disposition: the biological fate of chemicals 1997 May;25(5):617-22
  6. Adams JD Jr, Yagi H, Levin W, Jerina DM
    Stereo-selectivity and regio-selectivity in the metabolism of 7,8-dihydrobenzo[a]pyrene by cytochrome P450, epoxide hydrolase and hepatic microsomes from 3-methylcholanthrene-treated rats. Chemico-biological interactions 1995 Mar 30;95(1-2):57-77
  7. Gautier JC, Urban P, Beaune P, Pompon D
    Engineered yeast cells as model to study coupling between human xenobiotic metabolizing enzymes. Simulation of the two first steps of benzo[a]pyrene activation. European journal of biochemistry / FEBS 1993 Jan 15;211(1-2):63-72
  8. Taura Ki K, Yamada H, Naito E, Ariyoshi N, Mori Ma MA, Oguri K
    Activation of microsomal epoxide hydrolase by interaction with cytochromes P450: kinetic analysis of the association and substrate-specific activation of epoxide hydrolase function. Archives of biochemistry and biophysics 2002 Jun 15;402(2):275-80
  9. Raza H, Awasthi YC, Zaim MT, Eckert RL, Mukhtar H
    Glutathione S-transferases in human and rodent skin: multiple forms and species-specific expression. The Journal of investigative dermatology 1991 Apr;96(4):463-7
  10. Romert L, Dock L, Jenssen D, Jernstrom B
    Effects of glutathione transferase activity on benzo[a]pyrene 7,8-dihydrodiol metabolism and mutagenesis studied in a mammalian cell co-cultivation assay. Carcinogenesis 1989 Sep;10(9):1701-7
  11. Mojarrabi B, Mackenzie PI
    Characterization of two UDP glucuronosyltransferases that are predominantly expressed in human colon. Biochemical and biophysical research communications 1998 Jun 29;247(3):704-9
  12. Bock KW, Gschaidmeier H, Heel H, Lehmkoster T, Munzel PA, Bock-Hennig BS
    Functions and transcriptional regulation of PAH-inducible human UDP-glucuronosyltransferases. Drug metabolism reviews 1999 May;31(2):411-22
  13. Bock KW, Kohle C
    UDP-glucuronosyltransferase 1A6: structural, functional, and regulatory aspects. Methods in enzymology 2005;400:57-75

  1. Yun CH, Shimada T, Guengerich FP
    Roles of human liver cytochrome P4502C and 3A enzymes in the 3-hydroxylation of benzo(a)pyrene. Cancer research 1992 Apr 1;52(7):1868-74
  2. Bauer E, Guo Z, Ueng YF, Bell LC, Zeldin D, Guengerich FP
    Oxidation of benzo[a]pyrene by recombinant human cytochrome P450 enzymes. Chemical research in toxicology 1995 Jan-Feb;8(1):136-42
  3. Guo Z, Gillam EM, Ohmori S, Tukey RH, Guengerich FP
    Expression of modified human cytochrome P450 1A1 in Escherichia coli: effects of 5' substitution, stabilization, purification, spectral characterization, and catalytic properties. Archives of biochemistry and biophysics 1994 Aug 1;312(2):436-46
  4. Gautier JC, Lecoeur S, Cosme J, Perret A, Urban P, Beaune P, Pompon D
    Contribution of human cytochrome P450 to benzo[a]pyrene and benzo[a]pyrene-7,8-dihydrodiol metabolism, as predicted from heterologous expression in yeast. Pharmacogenetics 1996 Dec;6(6):489-99
  5. Shimada T, Gillam EM, Sutter TR, Strickland PT, Guengerich FP, Yamazaki H
    Oxidation of xenobiotics by recombinant human cytochrome P450 1B1. Drug metabolism and disposition: the biological fate of chemicals 1997 May;25(5):617-22
  6. Adams JD Jr, Yagi H, Levin W, Jerina DM
    Stereo-selectivity and regio-selectivity in the metabolism of 7,8-dihydrobenzo[a]pyrene by cytochrome P450, epoxide hydrolase and hepatic microsomes from 3-methylcholanthrene-treated rats. Chemico-biological interactions 1995 Mar 30;95(1-2):57-77
  7. Gautier JC, Urban P, Beaune P, Pompon D
    Engineered yeast cells as model to study coupling between human xenobiotic metabolizing enzymes. Simulation of the two first steps of benzo[a]pyrene activation. European journal of biochemistry / FEBS 1993 Jan 15;211(1-2):63-72
  8. Taura Ki K, Yamada H, Naito E, Ariyoshi N, Mori Ma MA, Oguri K
    Activation of microsomal epoxide hydrolase by interaction with cytochromes P450: kinetic analysis of the association and substrate-specific activation of epoxide hydrolase function. Archives of biochemistry and biophysics 2002 Jun 15;402(2):275-80
  9. Raza H, Awasthi YC, Zaim MT, Eckert RL, Mukhtar H
    Glutathione S-transferases in human and rodent skin: multiple forms and species-specific expression. The Journal of investigative dermatology 1991 Apr;96(4):463-7
  10. Romert L, Dock L, Jenssen D, Jernstrom B
    Effects of glutathione transferase activity on benzo[a]pyrene 7,8-dihydrodiol metabolism and mutagenesis studied in a mammalian cell co-cultivation assay. Carcinogenesis 1989 Sep;10(9):1701-7
  11. Mojarrabi B, Mackenzie PI
    Characterization of two UDP glucuronosyltransferases that are predominantly expressed in human colon. Biochemical and biophysical research communications 1998 Jun 29;247(3):704-9
  12. Bock KW, Gschaidmeier H, Heel H, Lehmkoster T, Munzel PA, Bock-Hennig BS
    Functions and transcriptional regulation of PAH-inducible human UDP-glucuronosyltransferases. Drug metabolism reviews 1999 May;31(2):411-22
  13. Bock KW, Kohle C
    UDP-glucuronosyltransferase 1A6: structural, functional, and regulatory aspects. Methods in enzymology 2005;400:57-75

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