title: Activation of p53 as a causal step for atherosclerosis induced by polycyclic aromatic hydrocarbons.
abstract: This study was performed to prove our hypothesis that the metabolite(s) of polycyclic aromatic hydrocarbons (PAHs) caused the activation or phosphorylation of p53 via DNA damage to suppress the liver X receptor (LXR)-mediated signal transductions as a probably more direct mechanism. We found that LXR-mediated trans-activation was inhibited by 3-methylchoranthrene (MC) and doxorubicin (Dox) in HepG2 cells carrying wild-type p53, but not in Hep3B cells possessing mutant p53. The exogenous expression of wild-type p53 suppressed the LXR-mediated trans-activation in Hep3B cells. The expression of mRNA for ATP binding cassette A1 was suppressed by MC and Dox in HepG2 cells. The protein expression of retinoid X receptor (RXR), a partner of LXR to form a heterodimer, was suppressed by MC and Dox in HepG2 cells.
authors.affiliation: Laboratory of Drug Metabolism, Graduate School of Pharmaceutical Sciences, Hokkaido University, N12W6, Sapporo, Hokkaido 060-0812, Japan.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Iwano
authors.forename: Norihito
authors.initials: N
authors.lastname: Shibahara
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Saito
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Kamataki
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000378:metabolism / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism*; D019281:Dimerization; D004317:Doxorubicin / Q000378:metabolism / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D000071518:Liver X Receptors; D008748:Methylcholanthrene / Q000378:metabolism / Q000494:pharmacology; D009154:Mutation; D057093:Orphan Nuclear Receptors; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D047488:Retinoid X Receptors / Q000096:biosynthesis; D015398:Signal Transduction / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000903:Antibiotics, Antineoplastic; D004268:DNA-Binding Proteins; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D047488:Retinoid X Receptors; D016159:Tumor Suppressor Protein p53; D008748:Methylcholanthrene; D004317:Doxorubicin