The effect of isothiocyanates on CYP1A1 and CYP1A2 activities induced by polycyclic aromatic hydrocarbons in Mcf7 cells.
Polycyclic aromatic hydrocarbons (PAHs)--environmental carcinogens--are metabolized by CYP1A1 and CYP1A2 enzymes to oxy-derivatives, which are able to bind to DNA and initiate carcinogenesis. PAHs induce CYP1A1 and CYP1A2 activity, which increases the risk of development of carcinogenesis. Isothiocyanates (ITCs), naturally occurring in Brassica vegetables, possess chemopreventive properties and are able to reduce the CYP1A enzyme activity. In this paper we report our study of the ability of ITCs: sulforaphane and its analogues: isothiocyanate-2-oxohexyl and alyssin, to inhibit CYP1A1 and CYP1A2 enzyme activity induced by the PAHs, anthracene (ANT) and dibenzo[a,h]anthracene (DBA) in human breast cancer cell line Mcf7. The aim was to determine whether the differences in structure of ITCs change their inhibitory properties, and whether these properties depend on the type of inducer. The results indicate that the properties of ITCs depend on the type of PAH: ITCs are more potent in inhibiting activity induced by the weaker inducer. It was also found that the change in ITCs' structure influences their activities. ITC 2-oxohexyl was the weakest inhibitor, whereas sulforaphane and alyssin exhibited similar potency. The study revealed that inhibition of CYP1A1 activity is direct whereas inhibition of CYP1A2 activity is not only direct but is also caused by the level of protein disturbance.
Skupinska
Katarzyna
K
National Medicines Institute, Chelmska 30/34, 00-725 Warsaw, Poland. skupinska@il.waw.pl
Misiewicz-Krzeminska
Irena
I
Lubelska
Katarzyna
K
Kasprzycka-Guttman
Teresa
T
D000873:Anthracenes / Q000633:toxicity*; D016588:Anticarcinogenic Agents / Q000737:chemistry / Q000494:pharmacology; D001551:Benz(a)Anthracenes / Q000633:toxicity; D001937:Brassica / Q000737:chemistry; D001943:Breast Neoplasms / Q000378:metabolism; D002273:Carcinogens / Q000633:toxicity; D045744:Cell Line, Tumor; D019363:Cytochrome P-450 CYP1A1 / Q000187:drug effects* / Q000378:metabolism; D019388:Cytochrome P-450 CYP1A2 / Q000187:drug effects* / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D006801:Humans; D017879:Isothiocyanates; D013329:Structure-Activity Relationship; D013454:Sulfoxides; D013861:Thiocyanates / Q000737:chemistry / Q000494:pharmacology*
C524315:2-oxohexyl isothiocyanate; D000873:Anthracenes; D016588:Anticarcinogenic Agents; D001551:Benz(a)Anthracenes; D002273:Carcinogens; D017879:Isothiocyanates; D013454:Sulfoxides; D013861:Thiocyanates; C524316:alyssin; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; C034020:anthracene; C016766:sulforaphane; C026486:1,2,5,6-dibenzanthracene