Curcumin attenuates cytochrome P450 induction in response to 2,3,7,8-tetrachlorodibenzo-p-dioxin by ROS-dependently degrading AhR and ARNT.
TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) is a highly toxic environmental contaminant. When exposed to TCDD, mammalian cells undergo malignant transformation via abnormal intracellular signaling cascades, and the robust inductions of cytochrome P450 (CYP) enzymes are considered to mediate carcinogenesis by producing genotoxic metabolites. We here examined whether curcumin has preventive activity against TCDD-induced CYP production and cell transformation. Initially, the cellular levels of cytochrome P450 (CYP) 1A1 and 1B1 were examined, because these are known to generate estrogen metabolites that mediate genotoxic stress. Curcumin inhibited CYP1A1 and 1B1 induction by TCDD at the mRNA and protein levels. Notably, the nuclear levels of arylhydrocarbon receptor (AhR) and AhR nuclear translocator (ARNT) were decreased by curcumin, but those in the cytoplasm were not. It was also found that oxidative stress mediated the curcumin-induced degradations of AhR and ARNT. Furthermore, in vitro transformation assays showed that in normal human embryonic kidney cells and normal prostate cells curcumin prevents the anchorage-independent growth induced by TCDD. In conclusion, curcumin attenuates AhR/ARNT-mediated CYP induction by dioxin and presumably this mode-of-action may be responsible for the curcumin prevention of malignant transformation. The findings of this study should be found helpful in the design stage of pharmacodynamic studies for developing curcumin as a chemopreventive or anticancer agent.
Choi
Hyunsung
H
Department of Pharmacology, Seoul National University College of Medicine, 28 Yongon-dong, Chongno-gu, Seoul 110-799, Korea.
Chun
Yang-Sook
YS
Shin
Yong Jae
YJ
Ye
Sang Kyu
SK
Kim
Myung-Suk
MS
Park
Jong-Wan
JW
D000952:Antigens, Polyomavirus Transforming / Q000502:physiology; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002472:Cell Transformation, Viral; D003474:Curcumin / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007668:Kidney / Q000166:cytology; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D034741:RNA, Small Interfering / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism
D000952:Antigens, Polyomavirus Transforming; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000072317:Polychlorinated Dibenzodioxins; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D003577:Cytochrome P-450 Enzyme System; D003474:Curcumin