Omeprazole and lansoprazole are mixed inducers of CYP1A and CYP3A in human hepatocytes in primary culture.
The ability of several gastric antiulcer drugs including lansoprazole, cimetidine and ranitidine to affect the expression of human liver microsomal cytochromes P450 comparatively to omeprazole, reported previously to be a CYP1A inducer, was evaluated in primary cultures of human hepatocytes. Poly (A)+ RNA and microsomes extracted from the cells were analyzed in Northern and Western blots with specific cDNA probes and antibodies, and assayed for form-specific monoxygenase activities. Lansoprazole induced both CYP1A1 and CYP1A2 as omeprazole and did not apparently bind to the aryl hydrocarbon receptor with high affinity. Omeprazole sulfone was not an inducer of CYP1A. Omeprazole, omeprazole sulfone and lansoprazole induced CYP3A in approximately 50% of tested cultures, whereas 100% of tested cultures responded to omeprazole and to rifampicin in terms of CYP1A and CYP3A induction, respectively. Finally, cimetidine and ranitidine were not inducers. We conclude that omeprazole and lansoprazole constitute a new class of mixed inducers of CYP1A and CYP3A in human hepatocytes in primary culture and that the induction of CYP3A in response to these molecules could be polymorphic in humans.
Curi-Pedrosa
R
R
Institut National de la Santé et de la Recherche Médicale U-128, Centre National de la Recherche Scientifique, Montpellier, France.
Daujat
M
M
Pichard
L
L
Ourlin
J C
JC
Clair
P
P
Gervot
L
L
Lesca
P
P
Domergue
J
J
Joyeux
H
H
Fourtanier
G
G
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors; D000328:Adult; D000368:Aged; D001189:Aryl Hydrocarbon Hydroxylases; D015152:Blotting, Northern; D015153:Blotting, Western; D002478:Cells, Cultured; D019363:Cytochrome P-450 CYP1A1; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000378:metabolism; D004790:Enzyme Induction; D005260:Female; D006801:Humans; D064747:Lansoprazole; D008099:Liver / Q000187:drug effects* / Q000201:enzymology*; D008297:Male; D008875:Middle Aged; D009853:Omeprazole / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D010088:Oxidoreductases / Q000096:biosynthesis* / Q000378:metabolism; D010089:Oxidoreductases, N-Demethylating / Q000096:biosynthesis* / Q000378:metabolism; D010105:Oxygenases / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D064747:Lansoprazole; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; D010105:Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; D019363:Cytochrome P-450 CYP1A1; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D000251:Adenosine Triphosphatases; D009853:Omeprazole