Tolbutamide and phenytoin hydroxylations by cDNA-expressed human liver cytochrome P4502C9

Veronese, Maurice E.; Mackenzie, Peter I.; Doecke, Christopher J; McManus, Michael E.; Miners, John O.; Birkett, Donald

doi:10.1016/0006-291x(91)91680-b

Cited by 184 publications

(94 citation statements)

References 16 publications

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“…4 Cytochrome P450 2C9 (CYP2C9) is expressed predominantly in the human liver, although it has also been detected in various extrahepatic tissues. 5 This is an important drug-metabolizing enzyme because it catalyzes the biotransformation of many clinically useful drugs, including phenytoin, 6 tolbutamide, 6,7 warfarin, 8 the alkylating anticancer prodrugs cyclophosphamide and ifosfamide, 9 and nonsteroidal anti-inflammatory drugs such as naproxen 10 and ibuprofen. 11 To date, several allelic variants of CYP2C9 have been identified.…”

Section: Introductionmentioning

confidence: 99%

Influence of CYP2C9 genotypes on the formation of a hepatotoxic metabolite of valproic acid in human liver microsomes

Abbott

Zanger

et al. 2003

Pharmacogenomics J

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The present study investigated the effect of cytochrome P450 2C9 (CYP2C9) genetic polymorphism on the biotransformation of valproic acid (VPA) to its hepatotoxic metabolite, 4-ene-VPA, and compared that to the formation of the inactive 4-OH-VPA and 5-OH-VPA. cDNA-expressed CYP2C9*2 and CYP2C9*3 variants were less efficient than the CYP2C9*1 wild type in catalyzing the formation of these metabolites, as assessed by the ratio of Vmax and apparent Km (in vitro intrinsic clearance). The reduced efficiency by CYP2C9*2 was due to a reduced Vmax, whereas, in the case of CYP2C9*3, it was the result of increased apparent Km. The formation rates of 4-ene-VPA, 4-OH-VPA, and 5-OH-VPA in human liver microsomes were reduced by 29, 28, and 31%, respectively, in samples with one mutated CYP2C9 allele, and by 61, 73, and 58%, respectively, in samples with two mutated CYP2C9 alleles. Overall, the homozygote and heterozygote CYP2C9*2 and CYP2C9*3 genotypes may compromise hepatic VPA biotransformation.

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Section: Introductionmentioning

confidence: 99%

Influence of CYP2C9 genotypes on the formation of a hepatotoxic metabolite of valproic acid in human liver microsomes

Abbott

Zanger

et al. 2003

Pharmacogenomics J

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“…Its hepatic metabolism is saturable and the P450IIC9 isozyme has been found to catalyse its hydroxylation [10]. Phenytoin is also extensively bound to plasma proteins.…”

Section: Introductionmentioning

confidence: 99%

The effect of tenidap sodium on the disposition and plasma protein binding of phenytoin in healthy male volunteers.

Blum

Schentag

Gardner

et al. 1995

Brit J Clinical Pharma

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“…The human CYP2C subfamily is well characterized and known to metabolize clinically important pharmaceuticals such as the hypoglycemic drug tolbutamide (Veronese et al, 1991;de Morais et al, 1994), the anticoagulant warfarin (Rettie et al, 1992) and nonsteroidal anti-inflammatory drugs such as diclofenac, ibuprofen, and acetylsalicylic acid (Leemann et al, 1993). Members of the human CYP2C subfamily also metabolize arachidonic acid (Daikh et al, 1994).…”

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confidence: 99%

CYP2C44, a New Murine CYP2C That Metabolizes Arachidonic Acid to Unique Stereospecific Products

DeLozier¹,

Tsao²,

Coulter³

et al. 2004

J Pharmacol Exp Ther

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The human CYP2Cs have been studied extensively with respect to the metabolism of clinically important drugs and endogenous chemicals such as arachidonic acid (AA). Five members of the mouse CYP2C family have previously been described that metabolize arachidonic acid into regio-and stereospecific epoxyeicosatrienoic acids (EETs) and hydroxyeicosatetraenoic acids, which have many important physiological roles. Herein, we describe the cloning and characterization of a new mouse cytochrome P450 (P450), CYP2C44, which has the lowest homology with other known mouse CYP2Cs. Western blotting and real-time polymerase chain reaction detected CYP2C44 mRNA and protein in liver Ͼ Ͼ kidney Ͼ adrenals. Kidney contained approximately 10% of the CYP2C44 mRNA content of liver. CYP2C44 metabolized AA to unique stereospecific products, 11R,12S-EET and 8R, 9S-EET, which are similar to those produced by rat CYP2C23. CY2C23 is highly expressed in rat kidney and has been suggested to be important in producing compensatory renal artery vasodilation in response to salt-loading in this species. Immunohistochemistry showed the presence of CYP2C44 in hepatocytes, biliary cells of the liver, and the proximal tubules of the kidney. Unlike mouse CYP2C29, CYP2C38, and CYP2C39, CYP2C44 did not metabolize the common CYP2C substrate tolbutamide. CYP2C44 was not induced by phenobarbital or pregnenolone-16␣-carbonitrile, two prototypical inducers of hepatic P450s. The presence of CYP2C44 in mouse liver, kidney, and adrenals and the unique stereospecificity of its arachidonic acid metabolites are consistent with the possibility that it may have unique physiological roles within these tissues, such as modulation of electrolyte transport or vascular tone.

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Tolbutamide and phenytoin hydroxylations by cDNA-expressed human liver cytochrome P4502C9

Cited by 184 publications

References 16 publications

Influence of CYP2C9 genotypes on the formation of a hepatotoxic metabolite of valproic acid in human liver microsomes

Influence of CYP2C9 genotypes on the formation of a hepatotoxic metabolite of valproic acid in human liver microsomes

The effect of tenidap sodium on the disposition and plasma protein binding of phenytoin in healthy male volunteers.

CYP2C44, a New Murine CYP2C That Metabolizes Arachidonic Acid to Unique Stereospecific Products

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