Structural toxicity relationship of 4-alkoxyphenols' cytotoxicity towards murine B16-F0 melanoma cell line.
OBJECTIVE
The aim of this study was to identify phenolic agents that could form quinone reactive intermediate metabolites in melanocytes in order to be effective as anti-melanoma agents; but were not metabolized by liver P450 metabolizing enzymes in order to have minimal toxicity towards the liver.


METHODS
Tyrosinase, an enzyme present abundantly in melanocytes was selected as a molecular target for the treatment of malignant melanoma. Ten alkoxyphenols were investigated for their metabolism by tyrosinase/O2, rat liver P450 microsomal/NADPH/O2 metabolizing systems and for their toxicity towards B16-F0 melanoma cells.


RESULTS
All the alkoxyphenols showed a dose- and time-dependent toxicity towards B16-F0 cells except 2-iso-propoxyphenol. 4-n-hexyloxyphenol demonstrated the greatest toxicity towards B16-F0 cells while minimally depleting glutathione in microsomal preparations at its calculated LC10 and LC50 lethal concentrations for B16-F0. At 100 microM concentrations, 4-t-butoxyphenol showed the lowest amount of glutathione depletion by microsomal P450 system. Alkoxyphenols with at least two alkyl groups derivatized at alpha carbon of alkoxy group showed minimal rates of metabolism by tyrosinase/O2 metabolizing system. A quantitative structural toxicity relationship equation was also derived, LogLC50(mM)= -0.265(+/-0.064)LogP + 2.482(+/-0.179).


CONCLUSIONS
4-n-hexyloxy-phenol was identified as a potential lead anti-melanoma agent against B16-F0 melanoma cells with minimal metabolism by rat liver P450 microsomal preparation.
Moridani
Majid Y
MY
Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University HSC, Amarillo, Texas 79106, USA. majid.moridani@ttuhsc.edu
Moore
Mike
M
Bartsch
Richard A
RA
Yang
Yanfei
Y
Heibati-Sadati
Souzan
S
D000438:Alcohols / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity*; D000818:Animals; D045744:Cell Line, Tumor; D008297:Male; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000378:metabolism*; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D010636:Phenols / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
D000438:Alcohols; D010636:Phenols; C059688:alkoxyl radical