Induction of cytochrome P-450 isozymes by chromanamine derivatives in rat liver.
1. Pretreatment of rats with 6-(3-picolyl)amino-2,2,5,8-tetramethylchromane (PATC) for 7 days resulted in a significant increase in the activities of benzphetamine N-demethylase, p-nitroanisole O-demethylase and aniline hydroxylase in liver microsomes prepared 24 h after the last treatment. 2. Analysis by Western blot showed that PATC induces cytochrome P-450 b, P-450 c and P-450 d, which are the major forms of cytochrome P-450 in liver microsomes of rats when pretreated with phenobarbital and 3-methylcholanthrene. 3. Exposure of liver sections to the antibodies to cytochrome P-450 b and P-450 c resulted in intense immunostaining within the centrilobular regions, but produced staining of considerably weaker intensity in the perilobular region. Semiquantitative immunochemical analysis, by image analyser, of cytochrome P-450 b and P-450 c showed that centrilobular hepatocytes were stained more intensively than perilobular hepatocytes. 4. These results indicate that PATC induces cytochromes P-450 b and P-450 c, in the centrilobular hepatocytes to a greater degree than those in the perilobular hepatocytes. 5. Co-administration of PATC with pentobarbital caused a significant increase in pentobarbital sleeping time. Furthermore, PATC was found to cause a decrease in the activity of benzphetamine N-demethylase in liver microsomes prepared 30 min after treatment with the drug.
Tsukidate
K
K
Tsukuba Research Laboratory, Eisai Co. Ltd, Ibaraki, Japan.
Sagami
F
F
Horie
T
T
Fukuda
T
T
Kitada
M
M
Kanakubo
Y
Y
D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology*; D002784:Cholesterol / Q000097:blood; D002839:Chromans / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000096:biosynthesis; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D010084:Oxidation-Reduction; D010424:Pentobarbital / Q000494:pharmacology; D004364:Pharmaceutical Preparations / Q000378:metabolism; D010847:Picolines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D012890:Sleep / Q000187:drug effects
D001578:Benzopyrans; D002839:Chromans; D007527:Isoenzymes; D004364:Pharmaceutical Preparations; D010847:Picolines; C061547:6-(3-picolyl)amino-2,2,5,8-tetramethylchromane; D003577:Cytochrome P-450 Enzyme System; D002784:Cholesterol; D006899:Mixed Function Oxygenases; D010424:Pentobarbital