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Titolo:
INHIBITION OF COUMARIN 7-HYDROXYLASE ACTIVITY IN HUMAN LIVER-MICROSOMES
Autore:
DRAPER AJ; MADAN A; PARKINSON A;
Indirizzi:
UNIV KANSAS,MED CTR,DEPT PHARMACOL TOXICOL & THERAPEUT,CTR ENVIRONM &OCCUPAT HLTH KANSAS CITY KS 66160 UNIV KANSAS,MED CTR,DEPT PHARMACOL TOXICOL & THERAPEUT,CTR ENVIRONM &OCCUPAT HLTH KANSAS CITY KS 66160
Titolo Testata:
Archives of biochemistry and biophysics
fascicolo: 1, volume: 341, anno: 1997,
pagine: 47 - 61
SICI:
0003-9861(1997)341:1<47:IOC7AI>2.0.ZU;2-B
Fonte:
ISI
Lingua:
ENG
Soggetto:
TORSADES-DE-POINTES; IN-VITRO; DRUG-METABOLISM; CYTOCHROME-P450-2A ENZYMES; DIFFERENTIAL INHIBITION; INVITRO INHIBITION; O-DEETHYLASE; CDNA; P450; CYTOCHROMES-P450;
Keywords:
CYTOCHROME P450, CHEMICAL INHIBITION; CYP2A6, CHEMICAL INHIBITION OF COUMARIN 7-HYDROXYLATION; INHIBITION OF HUMAN COUMARIN 7-HYDROXYLASE;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Science Citation Index Expanded
Citazioni:
58
Recensione:
Indirizzi per estratti:
Citazione:
A.J. Draper et al., "INHIBITION OF COUMARIN 7-HYDROXYLASE ACTIVITY IN HUMAN LIVER-MICROSOMES", Archives of biochemistry and biophysics, 341(1), 1997, pp. 47-61

Abstract

Nine organic solvents and 47 commonly used P450 substrates and inhibitors were examined for their effects on coumarin 7-hydroxylase (CYP2A6) activity in human liver microsomes. Of the nine organic solvents examined (final concentration 1%, v/v), only methanol did not inhibit the7-hydroxylation of coumarin (0.5 to 50 mu M) by human liver microsomes. Dioxane and tetrahydrofuran, which are structurally related to coumarin, were the most inhibitory solvents examined. Although the rates of coumarin 7-hydroxylation varied enormously among nine samples of human liver microsomes and cDNA-expressed CYP2A6 (V-max = 179 to 2470 pmol/mg protein/min), the K-m for coumarin 7-hydroxylation was fairly constant (ranging from 0.50 to 0.70 mu M). The following chemicals causedlittle or no inhibition of CYP2A6 as defined by a K-i > 200 mu M: caffeine, chlorzoxazone, cimetidine, dextromethorphan, diazepam, diclofenac, erythromycin, ethinylestradiol, ethynyltestosterone, fluconazole, furafylline, furfural, hexobarbital, itraconazole, mephenytoin, methimazole, metronidazole, naringenin, naringin, nifedipine, norfloxacin, norgestrel, orphenadrine, quinidine, papaverine, phenacetin, pyrimethamine, ranitidine, spironolactone, sulfaphenazole, sulfinpyrazone, testosterone, tolbutamide, troleandomycin, and warfarin. In other words, these chemicals, at a final concentration of 100 mu M, failed to inhibitCYP2A6 when the concentration of coumarin was equal to K-m (0.50 mu M). The following chemicals were classified as strong inhibitors of CYP2A6 (defined by K-i < 200 mu M): clotrimazole, diethyldithiocarbamate,ellipticine, ketoconazole, 8-methoxypsoralen, 4-methylpyrazole, metyrapone, miconazole, alpha-naphthoflavone, nicotine, p-nitrophenol, and tranylcypromine. The potency with which each chemical inhibited the 7-hydroxylation of coumarin was independent of which sample of human liver microsomes was studied. One of the most potent inhibitors of coumarin 7-hydroxylase was 8-methoxypsoralen (methoxsalen), which was determined to be a mechanism-based inhibitor (suicide substrate) of CYP2A6 (k(inactivation) 0.5 min(-1)). With the exception of 8-methoxypsoralen,preincubation of human liver microsomes and NADPH with the aforementioned inhibitors did not increase their ability to inhibit CYP2A6. The most potent competitive inhibitor of CYP2A6 was tranylcypromine (K-i =0.04 mu M). Several of the chemicals that strongly inhibited CYP2A6, such as ketoconazole and tranylcypromine, are often used with the intention of selectively inhibiting human P450 enzymes other than CYP2A6. The results of this study underscore the need for a systematic evaluation of the specificity of commonly used P450 inhibitors. (C) 1997 Academic Press.

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Documento generato il 07/08/20 alle ore 20:26:04