Disease relevance of Debrisoquin

• We conclude that the gene controlling debrisoquine 4-hydroxylation may be a host genetic determinant of susceptibility to lung cancer in smokers and that it represents a marker to assist in assessing individual risk [1].
• We report here the frequency of debrisoquine 4-hydroxylation phenotypes in age-, sex- and smoking history-matched bronchial carcinoma and control patients [1].
• Ecogenetics of Parkinson's disease: 4-hydroxylation of debrisoquine [2].
• We have studied by use of PCR and XbaI and EcoRI restriction-fragment-length polymorphism whether mutations at the polymorphic CYP2D6 (debrisoquine hydroxylase) gene locus are associated with liver cancer [3].
• Preliminary investigations have examined possible allelic associations, e.g., with alleles of MAO-A and debrisoquine hydroxylase and linkage to the tyrosine hydroxylase gene on chromosome 11p15.5 has been excluded in one study of juvenile familial parkinsonism [4].

Psychiatry related information on Debrisoquin

• In this study, we treated females of three rat species, which differ in their ability to hydroxylate debrisoquine, with MPTP (three doses of 30 mg/kg s.c. at 12-h intervals), and we measured their motor activity and brain monoamine levels [5].
• Debrisoquine hydroxylase gene polymorphism (CYP2D6*4) in dementia with Lewy bodies [6].
• Oxidation phenotyping was therefore undertaken, using debrisoquine in 100 alcoholic patients, 30 of whom had only fatty liver despite prolonged alcohol abuse, while the remaining 70 had alcoholic hepatitis and/or cirrhosis [7].
• Although debrisoquine hydroxylase (CYP2D6) capacity has been associated with personality, no study has specifically investigated its association with personality Type A and B. Therefore the aim of this research was to study the impact of CYP2D6 on Type A and B personality [8].
• Oxidative polymorphism of debrisoquine is not related to the risk of Alzheimer's disease [9].

High impact information on Debrisoquin

• The role of these enzymes in toxicological response is exemplified by an autosomal recessive polymorphism at the cytochrome P450 CYP2D6 debrisoquine hydroxylase locus which results in the severely compromised metabolism of at least 25 drugs, and which in some cases can lead to life-threatening side-effects [10].
• Recently, three genetic polymorphisms of human metabolic oxidation have been demonstrated (as characterized by debrisoquine, mephenytoin and carbocysteine), with the metabolism of several substrates exhibiting the phenomenon [1].
• Lung cancer and the debrisoquine metabolic phenotype [11].
• Mutant debrisoquine hydroxylation genes in Parkinson's disease [12].
• Debrisoquine hydroxylation phenotyping: do we expect too much [13]?

Chemical compound and disease context of Debrisoquin

• The responsiveness of plasma aldosterone to the infusion of angiotensin II at dose rates of 2, 4, and 10 ng/kg X min was assessed in 11 normal subjects and 13 patients with mild essential hypertension before and after 4 weeks of treatment with the sympatholytic agent debrisoquine [14].
• We conclude that there is no convincing evidence of an association between the debrisoquine/sparteine polymorphism and Parkinson's disease [15].
• The CYP2D6(C) P450, produced in HepG2 cells using vaccinia virus mediated cDNA expression displayed Km values toward bufuralol, debrisoquine and sparteine that were not significantly different from wild type CYP2D6 [16].
• The drug 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which induces parkinsonism in humans and in some animal models, is metabolized by cytochrome P450 db1 isozyme (the same enzymatic system implicated in 4-hydroxylation of debrisoquine) [5].
• The individual metabolic capacity was determined in 30 cluster headache patients after administration of a test dose of 10 mg of debrisoquine and 100 mg of mephenytoin [17].

Biological context of Debrisoquin

• Debrisoquine 4-hydroxylation segregates into two human phenotypes, each comprising characteristic metabolic capability [1].
• Polymorphic hydroxylation of debrisoquine [18].
• Disassociation between debrisoquine hydroxylation phenotype and genotype among Chinese [19].
• In the present study, we have investigated the molecular genetic basis for ultrarapid metabolism of debrisoquine [20].
• Previous linkage and association studies have suggested the presence of a susceptibility gene for AS close to, or within, the cytochrome P450 2D6 gene (CYP2D6, debrisoquine hydroxylase) located at chromosome 22q13 [21].

Anatomical context of Debrisoquin

• These studies indicate that genetically defective in vivo metabolism of debrisoquine is caused by a deficiency of a monooxygenase reaction in liver microsomes [22].
• The formation of the 4-hydroxy metabolite from debrisoquine in hepatic microsomes from extensive metabolizers was 1.33 +/- 0.437 nmol . mg protein-1 . 15 min-1 (mean +/- SD, n = 9) [22].
• Leukocyte DNA from "extensive metabolizers" (EMs) or "poor metabolizers" (PMs) of debrisoquine was examined by Southern analysis [23].
• Compared with unaffected individuals, patients suffering from BEN and/or urinary tract tumors were more frequently found to have a capacity for rapid debrisoquine (DB) metabolism, a metabolic reaction related mostly to cytochrome P450 (CYP) 2D in humans [24].
• No debrisoquin was detected in cerebrospinal fluid samples [25].

Associations of Debrisoquin with other chemical compounds

• Methoxyphenamine and dextromethorphan as safe probes for debrisoquine hydroxylation polymorphism [26].
• Hydroxylation of debrisoquine in patients with lacticacidosis after phenformin [27].
• To identify potential substrates for the debrisoquin and mephenytoin hydroxylation polymorphisms, we performed in vitro inhibition studies with human liver microsomes and the respective prototype substrates in the absence and presence of several anticancer drugs [28].
• The antibodies almost completely inhibited debrisoquine 4-hydroxylation and bufuralol 1'-hydroxylation in microsomes prepared from several different human livers [29].
• Using logistic regression analysis, efficient debrisoquine metabolism and a synergistic interaction between smoking and ethanol consumption were significant, independent risk factors, while S-mephenytoin hydroxylation and acetylation phenotype were not significant risk factors [30].

Gene context of Debrisoquin

• Multiple mutations of the human cytochrome P450IID6 gene (CYP2D6) in poor metabolizers of debrisoquine. Study of the functional significance of individual mutations by expression of chimeric genes [31].
• The disposition of racemic mephenytoin for CYP2C19 and debrisoquin for CYP2D6 were characterized in plasma and urine samples collected over 192 hours [32].
• METHODS: Single oral doses of 100 mg caffeine and 20 mg omeprazole were given separately to 5 EMs and 5 PMs of debrisoquin to assess the activity of CYP1A2 and CYP2C19, respectively [33].
• CYP2D6, but not CYP3A3/4, is subject to genetic polymorphism, which has been identified through the administration of a probe drug (sparteine, debrisoquin, or dextromethorphan) [34].
• 4-Hydroxylation of debrisoquine by human CYP1A1 and its inhibition by quinidine and quinine [35].

Analytical, diagnostic and therapeutic context of Debrisoquin

• In a case-control study, we tested the hypothesis that the genetically determined ability to metabolize debrisoquine is related to risk of lung cancer [11].
• Genotyping of poor metabolisers of debrisoquine by allele-specific PCR amplification [36].
• When TIQ 4-hydroxylase activity was compared in Wistar (an animal model of extensive debrisoquine metabolizers) and Dark Agouti (an animal model of poor debrisoquine metabolizers) rats, significant strain (Wistar greater than Dark Agouti) and sex (male greater than female) differences were observed [37].
• The median of the frequency distribution of the debrisoquine urinary recovery ratio in patients with aggressive bladder cancer was greater than in control subjects, and only four patients had recovery ratios lower than the mean of the control group [30].
• METHODS: Fluvoxamine (50 mg orally) was given to 10 extensive metabolizers and four poor metabolizers of debrisoquin, and concentrations were assessed in plasma by high performance liquid chromatography [38].

References