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Benzo[a]pyrene metabolism
Benzo[a]pyrene metabolism

Object List (links open in MetaCore):

11-Hydroxy- benzo[a]pyrene beta-D-glucuronoside, 1.14.14.1, HYEP, Benzo[a]pyrene- 7,8-diol, 11-Hydroxy- benzo[a]pyrene, CYP2C8, Benzo[a]pyrene- 4,5-oxide, 2.5.1.18, 1.14.14.1, 1.14.14.1, CYP1B1, 3-Hydroxy- benzo[a]pyrene, CYP1A2, 9-Hydroxy- benzo[a]pyrene- 4,5-oxide, Spontaneous, Benzo[a]pyrene, GSTP1, 1.14.14.1, 1.14.14.1, Benzo[a]pyrene 9,10-oxide, UGT1A10, 7,8-Dihydro- 7-hydroxy-8-S- glutathionyl- benzo[a]pyrene, 12-Hydroxy- benzo[a]pyrene beta-D-glucuronoside, BPDE, CYP2C9, Benzo[a]pyrene- 7,8-oxide, 9-Hydroxy- benzo[a]pyrene, CYP3A4, 3.3.2.9, 1.14.14.1, 2.4.1.17, UGT1A9, 2.4.1.17, UGT1A6, 2.5.1.18, DNA, CYP1A1, UGT1A7C Rat/Mouse, CYP2C18, 12-Hydroxy- benzo[a]pyrene, 1.14.14.1, 4,5-Dihydro- 4-hydroxy-5-S- glutathionyl- benzo[a]pyrene

Description

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 ) [13], [12].

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