Title
Inhibition of tolbutamide 4-methylhydroxylation by a series of non-steroidal anti-inflammatory drugs in V79-NH cells expressing human cytochrome P4502C10
Author
Kappers, W.A.
de Groene, E.M.
Kleij, L.A.
Witkamp, R.F.
Zweers-Zeilmaker, W.M.
Feron, V.J.
Horbach, G.J.
TNO Voeding
Publication year
1996
Abstract
1. To study the role of cytochrome P4502C10 in the metabolism of the non-steroidal antiinflammatory drugs (NSAIDs) diclofenac, phenylbutazone, fenoprofen, ibuprofen, flurbiprofen, ketoprofen and naproxen, a cell line was developed stably expressing CYP2C10 cDNA. A retroviral vector construct, containing a human CYP2C10 cDNA, was transfected in V79-NH Chinese hamster lung cells by calcium phosphate coprecipitation. Sublines stably expressing human cytochrome P450 cDNA were established by selection with the neomycin analogue G418. 2. Enzymatic activity of CYP2C10 was detected by 4-methylhydroxylation of tolbutamide. This activity was inhibited to background levels by preincubation with the CYP2C9/10 inhibitor sulphaphenazole. 3. Preincubations with the NSAIDs ketoprofen, phenylbutazone, flurbiprofen and diclofenac (all 250 μM) caused a decrease in 4-methylhydroxylation of tolbutamide (500 μM), significantly different from control values (p < 0.05). Inhibition of this activity was not seen in preincubations with the NSAIDs fenoprofen, ibuprofen and naproxen (250 αM). 4. The V79-NH CYP2C10 cell line we have developed has been shown to be a useful tool to predict drug-drug interactions.
Subject
Toxicology
CYP2C9 protein, human
cytochrome P450
diclofenac
enzyme inhibitor
flurbiprofen
ketoprofen
mixed function oxidase
nonsteroid antiinflammatory agent
phenylbutazone
sulfaphenazole
tolbutamide
tolbutamide 4 hydroxylase
tolbutamide 4-hydroxylase
unspecific monooxygenase
animal
article
cell line
Cricetulus
drug interaction
gene expression
genetic transfection
genetics
hamster
human
hydroxylation
lung
metabolism
methylation
Animals
Anti-Inflammatory Agents, Non-Steroidal
Aryl Hydrocarbon Hydroxylases
Cell Line
Cricetinae
Cricetulus
Cytochrome P-450 Enzyme System
Diclofenac
Drug Interactions
Enzyme Inhibitors
Flurbiprofen
Gene Expression
Humans
Hydroxylation
Ketoprofen
Lung
Methylation
Mixed Function Oxygenases
Phenylbutazone
Sulfaphenazole
Tolbutamide
Transfection
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http://resolver.tudelft.nl/uuid:41c452e9-4bc3-4059-9a78-69e76d68c7e1
TNO identifier
233653
ISSN
0049-8254
Source
Xenobiotica, 26 (12), 1231-1239
Document type
article