Inhibition of cytochromes P-450 and induction of glutathione S-transferases by sulforaphane in primary human and rat hepatocytes.
The isothiocyanate sulforaphane (SF) is thought to be a potential chemoprotective agent. Its effects on Phase I and Phase II enzymes of carcinogen metabolism in primary cultures of rat and human hepatocytes have been investigated. Northern blot analyses of rat hepatocytes showed a dose-dependent induction of mRNAs for rat glutathione S-transferases (rGSTs) A1/A2 and P1 but not M1. This was associated with enhanced levels of not only rGSTA1, A2, A4, A5, and P1 but also of rGSTs M1 and M2. On the other hand, the enzyme activities in rat hepatocytes associated with cytochromes P-450 (CYPs) 1A1 and 2B1/2, namely ethoxyresorufin-O-deethylase and pentoxyresorufin-O-dealkylase, respectively, were decreased in a dose-dependent manner. In SF-treated human hepatocytes, hGSTA1/2 but not hGSTM1 mRNAs were induced, and the expression of CYP1A2 was unaffected, whereas the expression of CYP3A4, the major CYP in human liver, was markedly decreased at both mRNA and activity levels. These observations demonstrate that in intact human and rat hepatocytes, SF may both induce a number of GSTs and cause enzyme inhibition of some but not all CYPs and, in the case of CYP3A4, inhibit both its enzyme activity and its expression.
Mahéo
K
K
INSERM U456, Détoxication et Réparation Tissulaire, Faculté des Sciences Pharmaceutiques et Biologiques, Université de Rennes I, France.
Morel
F
F
Langouët
S
S
Kramer
H
H
Le Ferrec
E
E
Ketterer
B
B
Guillouzo
A
A
D000328:Adult; D000818:Animals; D019363:Cytochrome P-450 CYP1A1 / Q000037:antagonists & inhibitors; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics / Q000378:metabolism; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D019362:Cytochrome P-450 CYP2B1 / Q000037:antagonists & inhibitors; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D005982:Glutathione Transferase / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D017879:Isothiocyanates; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D013454:Sulfoxides; D013861:Thiocyanates / Q000494:pharmacology*; D013997:Time Factors
D065609:Cytochrome P-450 CYP1A2 Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D018076:DNA, Complementary; D007527:Isoenzymes; D017879:Isothiocyanates; D012333:RNA, Messenger; D013454:Sulfoxides; D013861:Thiocyanates; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D019362:Cytochrome P-450 CYP2B1; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D005982:Glutathione Transferase; C016766:sulforaphane