Evidence for an enzymatic defect in the 4‐hydroxylation of debrisoquine by human liver.

Davies, DS; Kahn, GC; Murray, Stephen A.; Brodie, MJ; Boobis, AR

doi:10.1111/j.1365-2125.1981.tb01108.x

Cited by 91 publications

(26 citation statements)

References 8 publications

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“…It was thus desirable to investigate the oxidation of debrisoquine in vitro by microsomal fractions of human liver. Preliminary results of such studies showed that within a group of patients phenotyped in v'ivo the only liver biopsy sample with no detectable debrisoquine 4-hydroxylase activity was from the only patient phenotyped PM (Davies et al, 1981). Although our earlier work suggested that the activity was cytochrome P-450 mediated the data were not conclusive.…”

Section: Introductioncontrasting

confidence: 41%

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Assay and characterisation of debrisoquine 4‐hydroxylase activity of microsomal fractions of human liver.

Kahn¹,

Boobis²,

Murray³

et al. 1982

Brit J Clinical Pharma

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OHS1 A method for the assay of debrisoquine 4-hydroxylase activity in vitro by microsomal fractions of human liver is described. The assay utilises gas chromatography-mass spectrometry with d9-4-hydroxydebrisoquine as internal standard. 2 The limit of detection of 4-hydroxydebrisoquine was 2 ng ml land the coefficient of variation was 4.4%. 3 Debrisoquine 4-hydroxylase activity was linear with protein to concentrations above 2.1 mg mland with incubation times of at least 15 min. 4 Debrisoquine 4-hydroxylase is a microsomal enzyme with a requirement for NADPH. Activity was inhibited by carbon monoxide. It is concluded that the activity is catalysed by cytochrome P450. 5 In three samples of human liver the mean value for Vmax of debrisoquine 4-hydroxylase activity was 69.9 + 14.3 pmol mg-' min-m and for Km it was 130 + 24pM.6 The only variable from smoking status, alcohol ingestion, sex of the patients, source of liver sample and presence of liver disease that had a significant effect on 4-hydroxylation of debrisoquine was the presence of liver disease. This was associated with a decrease in enzyme activity.

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Section: Introductioncontrasting

confidence: 41%

“…Thus, the defect does not represent an alteration in all routes of oxidation. The oxidation of drugs such as amylobarbitone (Inaba et al, 1980), antipyrine (Tucker et al, 1977;Inaba et al, 1980;Davies et al, 1981) tolbutamide (Idle et al, 1979c) and acetanilide (Wakile et al, 1979) is totally unaffected by this locus.…”

Section: Introductionmentioning

confidence: 99%

Assay and characterisation of debrisoquine 4‐hydroxylase activity of microsomal fractions of human liver.

Kahn¹,

Boobis²,

Murray³

et al. 1982

Brit J Clinical Pharma

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“…There was a strong correlation between 4-hydroxylation of debrisoquine and 1'-hydroxylation of bufuralol. Both activities are impaired in the PM phenotype in vivo (Dayer et al, 1982) and reduced in biopsy samples from phenotyped PM subjects (Davies et al, 1981;Minder et al, 1983). Again, a strong correlation for the hydroxylation of debrisoquine and desmethylimipramine has been shown both in healthy subjects and in human liver microsomes (Spina et al, 1984).…”

Section: Resultsmentioning

confidence: 99%

Tolbutamide 4‐hydroxylase activity of human liver microsomes: effect of inhibitors.

Purba

Back

Orme

1987

Brit J Clinical Pharma

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Eight samples of human liver have been characterised for microsomal protein content, cytochrome P450 content, tolbutamide 4-hydroxylase and ethinyloestradiol 2-hydroxylase activities. Cytochrome P-450 content correlated significantly with ethinyloestradiol 2-hydroxylase activity but not with tolbutamide 4-hydroxylase activity. There was no significant correlation between ethinyloestradiol 2-hydroxylase and tolbutamide 4-hydroxylase activities. The maximum tolbutamide 4-hydroxylase activity was 0.45 nmol min-' mg-1 microsomal protein, with a Km value of 74 FLM. A number of compounds were tested for their ability to inhibit tolbutamide metabolism. All the compounds showing inhibition were either non-competitive or mixed non-competitive inhibitors of tolbutamide 4-hydroxylation. These studies suggest that tolbutamide is metabolised by an isozyme of cytochrome P-450 which appears to be distinct from those isozymes metabolising many other drugs.

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“…The implications of the foetal lack of cytochrome P450 IID6 are unknown. In adults, the only known implication is in the oxidation of a limited number of drug substrates (Davies et al, 1981;Gonzalez et al, 1988;Meyer et al, 1986). In some cases the deficiency of the IID6 isoenzyme leads to accumulation of the drug.…”

Section: Discussionmentioning

confidence: 99%

Differential foetal development of the O‐ and N‐demethylation of codeine and dextromethorphan in man.

Ladona

Lindström

Thyr

et al. 1991

Brit J Clinical Pharma

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Evidence for an enzymatic defect in the 4‐hydroxylation of debrisoquine by human liver.

Cited by 91 publications

References 8 publications

Assay and characterisation of debrisoquine 4‐hydroxylase activity of microsomal fractions of human liver.

Assay and characterisation of debrisoquine 4‐hydroxylase activity of microsomal fractions of human liver.

Tolbutamide 4‐hydroxylase activity of human liver microsomes: effect of inhibitors.

Differential foetal development of the O‐ and N‐demethylation of codeine and dextromethorphan in man.

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