The naturally occurring aliphatic isothiocyanates sulforaphane and erucin are weak agonists but potent non-competitive antagonists of the aryl hydrocarbon receptor.
As the Ah receptor target gene products play a critical role in chemical carcinogenesis, antagonists are considered as potential chemopreventive agents. It is demonstrated in this paper that the isothiocyanates R,S-sulforaphane and erucin are non-competitive antagonists of the aryl hydrocarbon (Ah) receptor. Both isothiocyanates were poor agonists for the receptor and elevated CYP1A1 mRNA levels only modestly when incubated with precision-cut rat liver slices. In contrast, the classical Ah receptor agonist benzo[a]pyrene was a potent inducer of CYP1A1 mRNA levels, with this effect being effectively antagonized by the two isothiocyanates. In further studies, it was demonstrated that R,S-sulforaphane could both prevent the interaction of and displace already bound benzo[a]pyrene from the Ah receptor, but no concentration dependency was observed with respect to the isothiocyanate. Both erucin and R,S-sulforaphane antagonized the benzo[a]pyrene-mediated increase in the CYP1A-mediated O-deethylation of ethoxyresorufin in rat precision-cut liver slices. Of the two isomers of R,S-sulforaphane, the naturally occurring R-isomer was more effective than the S-isomer in antagonizing the activation of the Ah receptor by benzo[a]pyrene. Antagonism of the Ah receptor may be a major contributor to the established chemoprevention of aliphatic isothiocyanates.
Molecular Toxicology Group, University of Surrey, Guildford, Surrey GU2 7XH, UK.
Ahmad F
AF
Abdull Razis
Natalya
N
Hanlon
Ewa
E
Soltys
Veronika
V
Krizova
Renato
R
Iori
Kathryn E
KE
Plant
Nick
N
Plant
Costas
C
Ioannides
D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D001564:Benzo(a)pyrene / Q000494:pharmacology; D019363:Cytochrome P-450 CYP1A1 / Q000187:drug effects* / Q000378:metabolism; D017879:Isothiocyanates; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D051379:Mice; D010078:Oxazines / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018336:Receptors, Aryl Hydrocarbon / Q000187:drug effects* / Q000378:metabolism; D013237:Stereoisomerism; D013440:Sulfides / Q000494:pharmacology*; D013454:Sulfoxides; D013861:Thiocyanates / Q000737:chemistry / Q000494:pharmacology*
D016588:Anticarcinogenic Agents; D000972:Antineoplastic Agents, Phytogenic; D017879:Isothiocyanates; D010078:Oxazines; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D013440:Sulfides; D013454:Sulfoxides; D013861:Thiocyanates; D001564:Benzo(a)pyrene; C007649:ethoxyresorufin; C073539:erucin; D019363:Cytochrome P-450 CYP1A1; C016766:sulforaphane