Linked Life Data

9811161

Source:http://linkedlifedata.com/resource/pubmed/id/9811161

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
9
pubmed:dateCreated
1999-1-8
pubmed:abstractText
The role of different cytochrome P450 isozymes (CYP) in the N-demethylation of chlorimipramine and chlorpromazine has been investigated in liver microsomes from rats by studying the effects of multiple subchronic doses of chlorimipramine, chlorpromazine, phenobarbital and beta-naphthoflavone on the N-demethylation of ethylmorphine, mono-N-demethyl-chlorimipramine and chlorpromazine and on the hydroxylation of aniline. With control microsomes, CYP-dependent metabolism of chlorimipramine and chlorpromazine (100 nmol; 30 min incubation) resulted in the formation of predominantly chlorimipramine (46.5 +/- 4.9 nmol) whereas chlorpromazine (14.1 +/- 0.9 nmol) accounted for only part of the overall metabolism of chlorpromazine. Multiple doses of chlorimipramine increased the capacity of microsomes to N-demethylate ethylmorphine (9.8 +/- 0.73 and 6.08 +/- 0.06 nmol min(-1) (mg protein)(-1) for chlorimipramine-treated and control rats, respectively) as well as itself (4.65 +/- 0.25 and 3.10 +/- 0.33 nmol min(-1) (mg protein)(-1), respectively). Multiple doses of chlorpromazine induced aniline-hydroxylase activity (1.11 +/- 0.16 and 0.94 +/- 0.06 nmol min(-1) (mg protein)(-1) for chlorimipramine and control microsomes, respectively) but the capacity to N-demethylate itself was unchanged. Phenobarbital treatment induced ethylmorphine N-demethylation activity, but did not affect N-demethylation activity, towards chlorimipramine and chlorpromazine. In control microsomes the N-demethylation capacity of chlorimipramine or chlorpromazine (0.160 +/- 0.025 and 0.015 +/- 0.003 nmol min(-1) (mg protein)(-1), respectively) was one order of magnitude lower than that of chlorimipramine or chlorpromazine. The capacity to N-demethylate either chlorimipramine or chlorpromazine was increased by treatment with either phenobarbital or beta-naphthoflavone. In control microsomes, sulphaphenazole markedly inhibited both chlorimipramine-N-mono- and di-N-demethylation, whereas quinidine markedly inhibited the rate of formation of chlorpromazine. The CYP2C and CYP2D subfamilies seem to be involved in the mono N-demethylation of chlorimipramine and chlorpromazine, respectively. Moreover the CYP1A and CYP2B subfamilies might participate in the N-demethylation of either chlorimipramine or chlorpromazine. This could have important implications in the clinical use of chlorimipramine and chlorpromazine in view of the genetic polymorphism of CYP2C and CYP2D isozymes in man.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Sep
pubmed:issn
0022-3573
pubmed:author
pubmed:issnType
Print
pubmed:volume
50
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1005-11
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed-meshheading:9811161-Animals, pubmed-meshheading:9811161-Anticonvulsants, pubmed-meshheading:9811161-Antidepressive Agents, Tricyclic, pubmed-meshheading:9811161-Antipsychotic Agents, pubmed-meshheading:9811161-Chlorpromazine, pubmed-meshheading:9811161-Clomipramine, pubmed-meshheading:9811161-Cytochrome P-450 Enzyme System, pubmed-meshheading:9811161-Dealkylation, pubmed-meshheading:9811161-Drug Interactions, pubmed-meshheading:9811161-Enzyme Inhibitors, pubmed-meshheading:9811161-Isoenzymes, pubmed-meshheading:9811161-Male, pubmed-meshheading:9811161-Microsomes, Liver, pubmed-meshheading:9811161-Phenobarbital, pubmed-meshheading:9811161-Rats, pubmed-meshheading:9811161-Rats, Sprague-Dawley, pubmed-meshheading:9811161-Substrate Specificity, pubmed-meshheading:9811161-beta-Naphthoflavone
pubmed:year
1998
pubmed:articleTitle
N-Dealkylation of chlorimipramine and chlorpromazine by rat liver microsomal cytochrome P450 isoenzymes.
pubmed:affiliation
Centro Interdipartimentale di Ricerca sul Metabolismo dei Farmaci Neuropsicotropi, Istituto di Scienze Farmacologiche, Università di Siena, Italy.
pubmed:publicationType
Journal Article, Comparative Study, Research Support, Non-U.S. Gov't