Modulation of carcinogen-metabolising cytochromes P450 in human liver by the chemopreventive phytochemical phenethyl isothiocyanate, a constituent of cruciferous vegetables.
On the basis of studies conducted in animals, it has been established that isothiocyanates suppress cytochrome P450 activity, leading to impairment of the bioactivation of carcinogens, this being a principal mechanism of their chemopreventive activity. However, no studies have been carried out in human tissue to ascertain whether hepatic cytochrome P450 composition is similarly modulated, and this is the objective of the present studies. Precision-cut liver slices from four donors were incubated with a range of concentrations of phenethyl isothiocyanate (PEITC) for 24h, and the expression and activity of cytochrome P450 enzymes were determined; similar studies were performed in rat slices for comparison. PEITC suppressed the O-dealkylation of methoxyresorufin in all human livers and this was accompanied by a parallel drop in CYP1A2 apoprotein levels; the same effect was noted in rat liver slices. The O-dealkylation of ethoxyresorufin was also impaired in the human livers, despite a rise in CYP1A1 apoprotein levels. The CYP3A-mediated benzyloxyquinoline dealkylation was inhibited by PEITC in only two of the four human donors, whereas a rise in CYP3A4 apoprotein levels was noted in all human livers, albeit to different extent. It is concluded that: (a) PEITC can modulate cytochrome P450 composition in human liver, and (b) PEITC, at concentrations that can be achieved by dietary intake, can antagonise the carcinogenicity of chemicals which rely on the CYP1 family for their bioactivation such as heterocyclic amines and polycyclic aromatic hydrocarbons, and this is likely to be a major contributory mechanism to its chemopreventive activity.
Konsue
Nattaya
N
Molecular Toxicology Group, Faculty of Health and Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UK.
Ioannides
Costas
C
D000328:Adult; D000368:Aged; D000818:Animals; D016588:Anticarcinogenic Agents / Q000737:chemistry / Q000494:pharmacology*; D002273:Carcinogens / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000378:metabolism; D017879:Isothiocyanates / Q000737:chemistry / Q000494:pharmacology*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000201:enzymology*; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014675:Vegetables / Q000737:chemistry*
D016588:Anticarcinogenic Agents; D002273:Carcinogens; D007527:Isoenzymes; D017879:Isothiocyanates; C058305:phenethyl isothiocyanate; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D007770:L-Lactate Dehydrogenase