Induction of cytochrome P450-1A by the equine estrogen equilenin, a new endogenous aryl hydrocarbon receptor ligand.
Equilenin is one of 10 kinds of estrogens that are found in pregnant mares' urine. It has been used extensively for estrogen replacement therapy in postmenopausal women. Typical inducers of the cytochrome P4501A1 (CYP1A1), such as TCDD, benzo(a)pyrene (B(a)P) and 3-methylcholanthrene, have a planar molecular structure in common and bind to the aryl hydrocarbon receptor (AhR). The structure of equilenin differs from classic estrogens by the presence of two additional double bonds in ring B of the steroid nucleus, and it is planar. This structural similarity of equilenin to the typical AhR agonist prompted us to investigate the capability of equilenin to induce CYP1A1 expression. Administration of equilenin to two mouse strains (C57BL and DBA) that exhibit different degrees of responsiveness to an Ah-receptor agonist and showed that equilenin was capable of dose-dependently increasing both the ethoxyresorufin O-deethylase activity and CYP1a proteins in both strains of mice. Equilenin also induced CYP1A1 mRNA in treated HepG2 cell lines and transcriptional activity in an XRE-directed luciferase reporter gene. Competitive binding studies using C57BL AhR indicated equilenin weakly displaced (3)H-B(a)P from AhR. Together, these data show that equilenin, an equine steroid hormone, served as an AhR ligand in the present study.
Jinno
Asumi
A
Laboratory of Toxicology, Department of Veterinary Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Kita 18, Nishi 9, Sapporo 060-0818, Japan.
Maruyama
Yutaka
Y
Ishizuka
Mayumi
M
Kazusaka
Akio
A
Nakamura
Akio
A
Fujita
Shoichi
S
D000818:Animals; D001667:Binding, Competitive; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000201:enzymology; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis* / Q000235:genetics; D004790:Enzyme Induction / Q000187:drug effects; D004855:Equilenin / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic; D006736:Horses; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000201:enzymology; D008024:Ligands; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation / Q000187:drug effects
D008024:Ligands; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D008156:Luciferases; D019363:Cytochrome P-450 CYP1A1; D004855:Equilenin