Activation of estrogen receptor alpha and ERbeta by 4-methylbenzylidene-camphor in human and rat cells: comparison with phyto- and xenoestrogens.
4-Methylbenzylidene-camphor (4-MBC) is an organic sunscreen that protects against UV radiation and may therefore help in the prevention of skin cancer. Recent results on the estrogenicity of 4-MBC have raised concerns about a potential of 4-MBC to act as an endocrine disruptor. Here, we investigated the direct interaction of 4-MBC with estrogen receptor (ER) alpha and ERbeta in a series of studies including receptor binding, ER transactivation and functional tests in human and rat cells. 4-MBC induced alkaline phosphatase activity, a surrogate marker for estrogenic activity, in human endometrial Ishikawa cells. Interestingly, 4-MBC induced weakly ERalpha and with a higher potency ERbeta mediated transactivation in Ishikawa cells at doses more than 1 microM, but showed no distinct binding affinity to ERalpha or ERbeta. In addition, 4-MBC was an effective antagonist for ERalpha and ERbeta. In an attempt to put 4-MBC's estrogenic activity into perspective we compared binding affinity and potency to activate ER with phyto- and xenoestrogens. 4-MBC showed lower estrogenic potency than genistein, coumestrol, resveratrol, bisphenol A and also camphor. Analysis of a potential metabolic activation of 4-MBC that could account for 4-MBC's more distinct estrogenic effects observed in vivo revealed that no estrogenic metabolites of 4-MBC are formed in primary rat or human hepatocytes. In conclusion, we were able to show that 4-MBC is able to induce ERalpha and ERbeta activity. However, for a hazard assessment of 4-MBC's estrogenic effects, the very high doses of 4-MBC required to elicit the reported effects, its anti-estrogenic properties as well as its low estrogenic potency compared to phytoestrogens and camphor has to be taken into account.
Mueller
Stefan O
SO
Institute of Toxicology, Merck KGaA, 64271 Darmstadt, Germany. stefan.o.mueller@merck.de
Kling
Margret
M
Arifin Firzani
Poppy
P
Mecky
Astrid
A
Duranti
Eric
E
Shields-Botella
Jacqueline
J
Delansorne
Remi
R
Broschard
Thomas
T
Kramer
Peter-Jürgen
PJ
D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology; D001597:Benzylidene Compounds / Q000494:pharmacology*; D002164:Camphor / Q000031:analogs & derivatives* / Q000494:pharmacology; D004054:Diethylstilbestrol / Q000494:pharmacology; D004717:Endometrium / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004958:Estradiol / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology*; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens / Q000494:pharmacology*; D004968:Estrogens, Non-Steroidal / Q000494:pharmacology; D005260:Female; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007529:Isoflavones; D008297:Male; D048789:Phytoestrogens; D028321:Plant Preparations; D051381:Rats; D017208:Rats, Wistar; D011960:Receptors, Estrogen / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism; D013473:Sunscreening Agents / Q000494:pharmacology*
D016588:Anticarcinogenic Agents; D001597:Benzylidene Compounds; D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens; D004968:Estrogens, Non-Steroidal; D007529:Isoflavones; D048789:Phytoestrogens; D028321:Plant Preparations; D011960:Receptors, Estrogen; D013473:Sunscreening Agents; D004958:Estradiol; D004054:Diethylstilbestrol; D002164:Camphor; D000469:Alkaline Phosphatase