Linked Life Data

15640373

Source:http://linkedlifedata.com/resource/pubmed/id/15640373

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
4
pubmed:dateCreated
2005-3-22
pubmed:abstractText
The enzymic basis for intracellular reduction of N-hydroxylated amidines to their corresponding amidines, and hydroxylamines to their corresponding amines, is unknown. The hydroxylated amidines can be used as prodrug moieties, and an understanding of the enzyme system active in the reduction can contribute to more efficient drug development. In this study, we examined the properties of this enzyme system using benzamidoxime and N-hydroxymelagatran as substrates. In rats and humans, the hepatic enzyme system was localized in mitochondria as well as in microsomes, using preferably NADH as cofactor. Potassium cyanide, N-methylhydroxylamine, p-hydroxymercuribenzoate, and desferrioxamine were efficient inhibitors, whereas typical cytochrome P450 (P450) inhibitors were ineffective. In rats, the highest specific activity was found in liver, adipose tissue, and kidneys, whereas in humans, the specific activity in the preparations of adipose tissue examined was lower. A sex difference was observed in rat liver, where 4-fold higher activity was seen in microsomes from female rats. No gender differences were present in any other tissue investigated. Partial purification of the hepatic system was achieved using polyethylene glycol fractionation followed by Octyl Sepharose chromatography at low detergent concentrations, whereas the enzyme was denatured after complete solubilization. The unique appearance of the enzyme activity in adipose tissue, together with the cyanide sensitivity and the failure of typical P450 inhibitors to impede the reaction, indicates that the enzyme system active in reduction of benzamidoxime and N-hydroxymelagatran formation is not of cytochrome P450 origin, but likely consists of an NADH-dependent electron transfer chain with a cyanide-sensitive protein as the terminal component.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Apr
pubmed:issn
0090-9556
pubmed:author
pubmed:issnType
Print
pubmed:volume
33
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
570-8
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed-meshheading:15640373-Adipose Tissue, pubmed-meshheading:15640373-Amidines, pubmed-meshheading:15640373-Animals, pubmed-meshheading:15640373-Azetidines, pubmed-meshheading:15640373-Benzamidines, pubmed-meshheading:15640373-Chemical Fractionation, pubmed-meshheading:15640373-Chromatography, Agarose, pubmed-meshheading:15640373-Cytochrome P-450 Enzyme System, pubmed-meshheading:15640373-Female, pubmed-meshheading:15640373-Humans, pubmed-meshheading:15640373-Kidney, pubmed-meshheading:15640373-Male, pubmed-meshheading:15640373-Microsomes, Liver, pubmed-meshheading:15640373-Mitochondria, Liver, pubmed-meshheading:15640373-Organ Specificity, pubmed-meshheading:15640373-Oxidation-Reduction, pubmed-meshheading:15640373-Oxidoreductases, pubmed-meshheading:15640373-Rats, pubmed-meshheading:15640373-Sex Factors, pubmed-meshheading:15640373-Species Specificity, pubmed-meshheading:15640373-Substrate Specificity
pubmed:year
2005
pubmed:articleTitle
Characterization and partial purification of the rat and human enzyme systems active in the reduction of N-hydroxymelagatran and benzamidoxime.
pubmed:affiliation
Division of Molecular Toxicology, IMM, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
pubmed:publicationType
Journal Article, In Vitro, Research Support, Non-U.S. Gov't