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Induction of cytochrome P450 by Nrf2 activators: Implication for aldehyde metabolism
Author(s) -
Amunom Immaculate,
Stephens Laura J.,
Conklin Daniel J.,
Prough Russell A
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a261-a
Subject(s) - acrolein , aldehyde dehydrogenase , chemistry , aldehyde , microsome , biochemistry , metabolism , cytochrome p450 , lipid peroxidation , aldh2 , activator (genetics) , enzyme , gene , catalysis
Acrolein is an environmental pollutant and product of lipid peroxidation in vivo . Acrolein mediates the activation of Nrf2, so we sought to determine whether Nrf2 regulates clearance of acrolein by inducing specific hepatic P450s. The routes of metabolism of acrolein and α,β‐unsaturated aldehydes include carboxylic acid and alcohol formation. C57BL/6 mice were fed either 5 mg/kg of acrolein by gavage for 72 h or AIN76 diet containing 0.45 % BHA, a Nrf2 activator, for 7 days. Mouse liver was frozen at −80 ° and after extraction, the RNA was reverse transcribed to cDNA. Cyp2c29 mRNA levels were analyzed by QRT‐PCR. Liver microsomal protein fractions were prepared from control or BHA‐fed mouse liver. Our results indicate that hepatic Cyp2c29 mRNA levels were induced 5‐fold in BHA‐treated mice and 2‐fold in acrolein‐treated mice. Likewise, there was a two‐fold higher activity for 9‐anthracene aldehyde oxidation to 9‐anthracene carboxylic acid and reduction to 9‐anthracene methanol with BHA‐treated mouse liver microsomes, reactions catalyzed by Cyp2c29 expressed in E. coli . These reactions were inhibited 90% by 0.5 mM miconazole, a general P450 inhibitor, but only slightly inhibited by troleandomycin, a Cyp3a11‐specific inhibitor or cyanamide, an aldehyde dehydrogenase inhibitor. Cyp3A11 mRNA levels remained unchanged upon BHA feeding. This suggests that the aldehyde oxidation and reduction activity present in murine hepatic microsomes is predominantly mediated by Cyp2c29. Supported by USPHS P01 ES11860.