Linked Life Data

1981725

Source:http://linkedlifedata.com/resource/pubmed/id/1981725

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
5
pubmed:dateCreated
1991-4-25
pubmed:abstractText
Oxidative metabolism of diltiazem (DTZ), a calcium channel blocker, was investigated in rabbit and human liver microsomes as well as in primary cultures of human hepatocytes. DTZ N-demethylation, the major metabolic pathway in man, was strongly increased by treatment of animals, patients, and hepatocyte cultures with rifampicin and other inducers of the P-450IIIA subfamily. In a reconstituted system with purified forms of P-450 and NADPH cytochrome P-450 reductase, P-450IIIA7 exhibited the highest DTZ N-demethylase activity. In both rabbit and human liver microsomes, this activity was highly correlated with erythromycin demethylase, a characteristic substrate of P-450IIIA, or with an immunoquantitated level of P-450IIIA, and was specifically inhibited by anti-P-450IIIA7 polyclonal and monoclonal antibodies. Cyclosporin A, another specific substrate of P-450IIIA in rabbit and human, competitively inhibited DTZ N-demethylase in both species. In primary cultures of human hepatocytes treated with various inducers, including rifampicin, dexamethasone, phenobarbital, phenylbutazone or beta-naphthoflavone, the rate of release of N-demethyl-DTZ in the extracellular medium was highly correlated with the intracellular level of P-450IIIA, which appeared to be strongly induced by rifampicin and phenobarbital and to a lesser extent by dexamethasone and phenylbutazone. In aggregate, these results are consistent with the view that in both rabbit and human, cytochromes P-450 from the P-450IIIA subfamily are the major enzymes involved in the N-demethylation of DTZ. Accordingly, drugs which may be specific substrates or inducers of this P-450 are likely to influence both the side effects and the efficacy of this molecule.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:issn
0090-9556
pubmed:author
pubmed:issnType
Print
pubmed:volume
18
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
711-9
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed-meshheading:1981725-Adult, pubmed-meshheading:1981725-Aged, pubmed-meshheading:1981725-Animals, pubmed-meshheading:1981725-Aryl Hydrocarbon Hydroxylases, pubmed-meshheading:1981725-Blotting, Western, pubmed-meshheading:1981725-Cells, Cultured, pubmed-meshheading:1981725-Chromatography, High Pressure Liquid, pubmed-meshheading:1981725-Cyclosporins, pubmed-meshheading:1981725-Cytochrome P-450 CYP3A, pubmed-meshheading:1981725-Cytochrome P-450 Enzyme System, pubmed-meshheading:1981725-Dealkylation, pubmed-meshheading:1981725-Diltiazem, pubmed-meshheading:1981725-Enzyme Induction, pubmed-meshheading:1981725-Female, pubmed-meshheading:1981725-Humans, pubmed-meshheading:1981725-Isoenzymes, pubmed-meshheading:1981725-Liver, pubmed-meshheading:1981725-Male, pubmed-meshheading:1981725-Middle Aged, pubmed-meshheading:1981725-Mixed Function Oxygenases, pubmed-meshheading:1981725-NADPH-Ferrihemoprotein Reductase, pubmed-meshheading:1981725-Oxidoreductases, N-Demethylating, pubmed-meshheading:1981725-Rabbits
pubmed:articleTitle
Identification of the rabbit and human cytochromes P-450IIIA as the major enzymes involved in the N-demethylation of diltiazem.
pubmed:affiliation
Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique, Montpellier, France.
pubmed:publicationType
Journal Article, In Vitro, Research Support, Non-U.S. Gov't