Up-regulation of the CYP1 family in rat and human liver by the aliphatic isothiocyanates erucin and sulforaphane.
On the basis of animal studies, the chemopreventive activity of isothiocyanates has been linked to their ability to modulate carcinogen-metabolising enzyme systems, including cytochrome P450. However, the potential of isothiocyanates to influence these enzyme systems in human liver has not been investigated. We have evaluated the modulation of cytochrome P450 expression in two human liver samples by erucin and sulforaphane, in comparison to rat, following the incubation of precision-cut human and rat liver slices with the two isothiocyanates. Both compounds failed to influence cytochrome P450 activity, as exemplified by the dealkylations of methoxy-, ethoxy- and pentoxyresorufin, and benzyloxyquinoline, in either human or rat liver. Impairment of activity was, however, observed in some activities at high concentrations (50microM), which was attributed to toxicity. At the apoprotein level, however, both compounds markedly elevated CYP1A2/1B1 levels in rat liver, but in human liver only a modest increase was evident, and only in one of the livers. CYP3A2 apoprotein levels were modestly elevated in rat liver by both isothiocyanates both of which, however, failed to influence CYP3A4 expression in human liver. Neither isothiocyanate, in either rat or human liver, modulated CYP2B apoprotein levels. It may be inferred that (a) human and rat liver differ in their response to erucin and sulforaphane, (b) erucin and sulforaphane, despite being small molecular weight aliphatic compounds, up-regulate the CYP1 family but no increase in activity is observed as a result of mechanism-based inhibition, and (c) the chemopreventive effect of isothiocyanates, at dietary levels of intake, is unlikely to be due to inhibition of the cytochrome P450-mediated bioactivation of carcinogens.
Hanlon
Natalya
N
Centre of Toxicology, Faculty of Health and Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UK.
Coldham
Nick
N
Sauer
Maurice J
MJ
Ioannides
Costas
C
D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004032:Diet; D006801:Humans; D066298:In Vitro Techniques; D017879:Isothiocyanates; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D013045:Species Specificity; D013440:Sulfides / Q000494:pharmacology*; D013454:Sulfoxides; D013861:Thiocyanates / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
D016588:Anticarcinogenic Agents; D017879:Isothiocyanates; D013440:Sulfides; D013454:Sulfoxides; D013861:Thiocyanates; D003577:Cytochrome P-450 Enzyme System; C073539:erucin; C016766:sulforaphane