title: Oxidation of PAH trans-dihydrodiols by human aldo-keto reductase AKR1B10.
abstract: AKR1B10 has been identified as a potential biomarker for human nonsmall cell lung carcinoma and as a tobacco exposure and response gene. AKR1B10 functions as an efficient retinal reductase in vitro and may regulate retinoic acid homeostasis. However, the possibility that this enzyme is able to activate polycyclic aromatic hydrocarbon (PAH) trans-dihydrodiols to form reactive and redox-active o-quinones has not been investigated to date. AKR1B10 was found to oxidize a wide range of PAH trans-dihydrodiol substrates in vitro to yield PAH o-quinones. Reactions of AKR1B10 proceeded with improper stereochemistry, since it was specific for the minor (+)-benzo[a]pyrene-7S,8S-dihydrodiol diastereomer formed in vivo. However, AKR1B10 displayed reasonable activity in the oxidation of both the (-)-R,R and (+)-S,S stereoisomers of benzo[g]chrysene-11,12-dihydrodiol and oxidized the potentially relevant, albeit minor, (+)-benz[a]anthracene-3S,4S-dihydrodiol metabolite. We find that AKR1B10 is therefore likely to play a contributing role in the activation of PAH trans-dihydrodiols in human lung. AKR1B10 retinal reductase activity was confirmed in vitro and found to be 5- to 150-fold greater than the oxidation of PAH trans-dihydrodiols examined. AKR1B10 was highly expressed at the mRNA and protein levels in human lung adenocarcinoma A549 cells, and robust retinal reductase activity was measured in lysates of these cells. The much greater catalytic efficiency of retinal reduction compared to PAH trans-dihydrodiol metabolism suggests AKR1B10 may play a greater role in lung carcinogenesis through dysregulation of retinoic acid homeostasis than through oxidation of PAH trans-dihydrodiols.
authors.affiliation: Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6084, USA.
authors.forename: Amy M
authors.initials: AM
authors.lastname: Quinn
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Harvey
authors.forename: Trevor M
authors.initials: TM
authors.lastname: Penning
mesh_terms: D000449:Aldehyde Reductase / Q000032:analysis / Q000502:physiology*; D000074408:Aldo-Keto Reductases; D002273:Carcinogens / Q000378:metabolism*; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology; D002478:Cells, Cultured; D002942:Circular Dichroism; D004101:Dihydroxydihydrobenzopyrenes / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000209:etiology; D010084:Oxidation-Reduction; D011084:Polycyclic Aromatic Hydrocarbons / Q000378:metabolism*; D012172:Retinaldehyde / Q000378:metabolism
chemical_list: D002273:Carcinogens; D004101:Dihydroxydihydrobenzopyrenes; D011084:Polycyclic Aromatic Hydrocarbons; C017228:benzo(a)pyrene 7,8-dihydrodiol; C120471:AKR1B10 protein, human; D000074408:Aldo-Keto Reductases; D000449:Aldehyde Reductase; D012172:Retinaldehyde
references.citation: J Org Chem. 2004 Mar 19;69(6):2024-32
references.pmid: 15058949
references.citation: Int J Cancer. 2007 Nov 15;121(10):2301-6
references.pmid: 17597105
references.citation: Chem Res Toxicol. 1996 Jan-Feb;9(1):84-92
references.pmid: 8924621
references.citation: Free Radic Biol Med. 2000 Jul 1;29(1):17-25
references.pmid: 10962201
references.citation: Carcinogenesis. 1998 Nov;19(11):1889-94
references.pmid: 9854998
references.citation: J Natl Cancer Inst. 1997 May 7;89(9):624-9
references.pmid: 9150186
references.citation: J Clin Endocrinol Metab. 1998 Aug;83(8):2886-91
references.pmid: 9709964
references.citation: Chem Res Toxicol. 1993 May-Jun;6(3):252-60
references.pmid: 7686407
references.citation: Cancer Res. 2000 Feb 15;60(4):908-15
references.pmid: 10706104
references.citation: J Natl Cancer Inst. 2005 Nov 16;97(22):1645-51
references.pmid: 16288117
references.citation: Biochemistry. 1996 Oct 22;35(42):13664-72
references.pmid: 8885846
references.citation: Cancer Res. 1997 Nov 1;57(21):4931-9
references.pmid: 9354460
references.citation: Environ Sci Technol. 2005 Jan 15;39(2):471-8
references.pmid: 15707046
references.citation: Nature. 1990 Jan 11;343(6254):177-80
references.pmid: 2153268
references.citation: Chem Biol Interact. 1984 Apr;49(1-2):71-88
references.pmid: 6722941
references.citation: FASEB J. 1997 Feb;11(2):181-8
references.pmid: 9039961
references.citation: Toxicol Lett. 2004 Sep 25;152(3):235-43
references.pmid: 15331132
references.citation: Cancer Prev Res (Phila). 2008 Jul;1(2):80-3
references.pmid: 19138939
references.citation: EMBO J. 1989 Feb;8(2):429-33
references.pmid: 2542014
references.citation: Mol Carcinog. 1993;8(2):112-22
references.pmid: 7691069
references.citation: Clin Cancer Res. 2005 Mar 1;11(5):1776-85
references.pmid: 15755999
references.citation: Arch Biochem Biophys. 2007 Aug 15;464(2):241-50
references.pmid: 17537398
references.citation: Xenobiotica. 1996 Sep;26(9):909-19
references.pmid: 8893038
references.citation: Chem Biol Interact. 1979 Oct;27(2-3):145-61
references.pmid: 498352
references.citation: Biochemistry. 2001 Sep 11;40(36):10901-10
references.pmid: 11535067
references.citation: Mol Cell Endocrinol. 2008 Jan 16;281(1-2):1-8
references.pmid: 18060684
references.citation: Cancer Res. 1995 Dec 1;55(23):5603-10
references.pmid: 7585641
references.citation: Nutr Rev. 1999 Sep;57(9 Pt 1):263-72
references.pmid: 10568335
references.citation: IARC Monogr Eval Carcinog Risk Chem Hum. 1983 Dec;32:1-453
references.pmid: 6586639
references.citation: Biochem J. 2006 Oct 1;399(1):101-9
references.pmid: 16787387
references.citation: J Nutr. 2000 Feb;130(2S Suppl):479S-482S
references.pmid: 10721933
references.citation: Chem Res Toxicol. 2008 May;21(5):1086-94
references.pmid: 18402469
references.citation: Cancer Res. 2007 Aug 1;67(15):7431-8
references.pmid: 17671213
references.citation: Chem Res Toxicol. 2005 Feb;18(2):365-74
references.pmid: 15720144
references.citation: N Engl J Med. 1996 May 2;334(18):1150-5
references.pmid: 8602180
references.citation: Lung Cancer. 2004 Sep;45(3):289-97
references.pmid: 15301869
references.citation: Carcinogenesis. 1982;3(2):215-7
references.pmid: 7067048
references.citation: Biochem J. 1999 Oct 15;343 Pt 2:487-504
references.pmid: 10510318
references.citation: Cancer Prev Res (Phila). 2008 Jul;1(2):112-8
references.pmid: 19138944
references.citation: Cell Prolif. 2007 Jun;40(3):411-21
references.pmid: 17531084
references.citation: Endocrinology. 2006 Dec;147(12):5806-16
references.pmid: 16959841
references.citation: N Engl J Med. 1994 Apr 14;330(15):1029-35
references.pmid: 8127329
references.citation: J Biol Chem. 2002 Jul 5;277(27):24799-808
references.pmid: 11978787
references.citation: Chem Biol Interact. 1983 Jul 1;45(1):15-28
references.pmid: 6872097
references.citation: Biochemistry. 1998 May 12;37(19):6781-90
references.pmid: 9578563
references.citation: Pharmacol Ther. 1992;54(1):63-128
references.pmid: 1528955
references.citation: Proc Natl Acad Sci U S A. 2008 May 13;105(19):6846-51
references.pmid: 18474869
references.citation: Chem Res Toxicol. 2006 Jan;19(1):68-78
references.pmid: 16411658
references.citation: Cancer Res. 2004 Dec 15;64(24):9027-34
references.pmid: 15604268
references.citation: Biochem J. 2003 Aug 1;373(Pt 3):973-9
references.pmid: 12732097
references.citation: J Biol Chem. 1993 Dec 5;268(34):25687-93
references.pmid: 8245005
references.citation: J Natl Cancer Inst. 1999 Jun 16;91(12):1059-66
references.pmid: 10379969
references.citation: J Neurobiol. 2006 Jun;66(7):606-30
references.pmid: 16688755
references.citation: FASEB J. 1989 Jun;3(8):1927-32
references.pmid: 2656356
references.citation: J Biol Chem. 1998 May 8;273(19):11429-35
references.pmid: 9565553
references.citation: Carcinogenesis. 1991 Oct;12(10):1939-44
references.pmid: 1934274
references.citation: Carcinogenesis. 2005 Mar;26(3):525-30
references.pmid: 15618235
references.citation: Toxicol Lett. 2006 Aug 20;165(2):182-94
references.pmid: 16713138
references.citation: J Pathol. 2006 Oct;210(2):192-204
references.pmid: 16915569
references.citation: Am Ind Hyg Assoc J. 1965 Sep-Oct;26(5):475-8
references.pmid: 5865317
references.citation: Chem Res Toxicol. 2006 May;19(5):719-28
references.pmid: 16696575
references.citation: Cancer Prev Res (Phila). 2008 Jul;1(2):100-11
references.pmid: 19138943
references.citation: Hepatology. 2004 Feb;39(2):540-9
references.pmid: 14768008