CYP1A1-mediated mechanism for atherosclerosis induced by polycyclic aromatic hydrocarbons.
Polycyclic aromatic hydrocarbons (PAHs) have been known to induce atherosclerosis. It has been reported that the metabolic activation of PAHs by cytochrome P450 (CYP) is an important step for PAH-induced atherosclerosis. We recently reported that PAHs down-regulated the liver X receptor (LXR) alpha-regulated genes via aryl hydrocarbon receptor (AHR) as one of the causes responsible for atherosclerosis induced by PAHs. Thus, the aim of this study was to clarify the role of CYP1A1 in the suppression of LXR-mediated signal transductions by 3-methlychoranthrene (MC), one of the PAHs. We found that LXR-mediated transactivation was inhibited by the PAH, but not by halogenated aromatic hydrocarbon, which is scarcely metabolized by CYP1A1. The repression of LXR-mediated signal transductions by MC was restored by co-treatment of HepG2 cells with a CYP1A1 inhibitor, alpha-naphthoflavone, and by the transfection of short interference RNA for CYP1A1. Based on these lines of evidence, we propose that the metabolic activation of PAHs by CYP1A1, but not the activation of AHR by PAHs, is a direct mechanism for atherosclerosis via the suppression of LXR-mediated signal transductions.
Iwano
Shunsuke
S
Laboratory of Drug Metabolism, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
Asanuma
Fumie
F
Nukaya
Manabu
M
Saito
Tetsuya
T
Kamataki
Tetsuya
T
D000818:Animals; D050197:Atherosclerosis / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism; D001551:Benz(a)Anthracenes / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000378:metabolism; D045744:Cell Line, Tumor; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D004790:Enzyme Induction; D006846:Hydrocarbons, Halogenated / Q000494:pharmacology; D000071518:Liver X Receptors; D008156:Luciferases / Q000378:metabolism; D057093:Orphan Nuclear Receptors; D011084:Polycyclic Aromatic Hydrocarbons; D034741:RNA, Small Interfering / Q000235:genetics; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D014162:Transfection
C504364:3-methlycholanthrene; D001551:Benz(a)Anthracenes; D004268:DNA-Binding Proteins; D006846:Hydrocarbons, Halogenated; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D011084:Polycyclic Aromatic Hydrocarbons; D034741:RNA, Small Interfering; D018336:Receptors, Aryl Hydrocarbon; D018160:Receptors, Cytoplasmic and Nuclear; D008156:Luciferases; D019363:Cytochrome P-450 CYP1A1