Genetic polymorphism in drug oxidation: In vitro studies of human debrisoquine 4-hydroxylase and bufuralol 1′-hydroxylase activities

Boobis, Alan R.; Murray, Stephen A.; Hampden, Caroline E.; Davies, Donald S.

doi:10.1016/0006-2952(85)90101-7

Cited by 62 publications

(22 citation statements)

References 8 publications

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“…mean *P < 0.05, **P < 0.01., smokers (E3) The oxidation of over 14 compounds has now been shown to be impaired in the PM phenotype. The possibility that there are multiple linked polymorphisms has largely been discounted as a result of a number of studies on mutual inhibition conducted in vitro (Boobis et al, 1983(Boobis et al, , 1985Otton et al, 1982Otton et al, , 1983Otton et al, , 1984Spina et al, 1984;von Bahr et al, 1985). All the substrates tested, with the exception of phenacetin in the present report, have been shown to be potent competitive inhibitors of the oxidation of debrisoquine, sparteine or desmethylimipramine.…”

Section: Discussionmentioning

confidence: 99%

Phenacetin O‐deethylase: an activity of a cytochrome P‐450 showing genetic linkage with that catalysing the 4‐hydroxylation of debrisoquine?

Kahn¹,

Boobis²,

Brodie³

et al. 1985

Brit J Clinical Pharma

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1 Phenacetin O-deethylase activity was impaired, both in vivo and in vitro, in poor metabolisers of debrisoquine, consistent with the work of others. No impairment was observed in the oxidation of acetanilide, amylobarbitone or antipyrine in the PM phenotype. 2 There was a good correlation (r = 0.804) between the high affinity component of phenacetin O-deethylase and debrisoquine 4-hydroxylase activities. No such correlation was observed with the low affinity component of phenacetin O-deethylase activity. 3 Although debrisoquine was a competitive inhibitor of phenacetin O-deethylase activity, phenacetin was without effect on debrisoquine 4-hydroxylation. There were also marked differences in the effects of sparteine, guanoxan and a-naphthoflavone on the two activities. 4 Cigarette smoking was associated with a significant, two-fold, increase in phenacetin O-deethylase activity whilst debrisoquine 4-hydroxylase activity was not affected. 5 It is concluded that the high affinity component of phenacetin O-deethylase and debrisoquine 4-hydroxylase activities are catalysed by different isozymes of cytochrome P-450 but that these are most probably regulated by closely linked genes.

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Section: Discussionmentioning

confidence: 99%

Phenacetin O‐deethylase: an activity of a cytochrome P‐450 showing genetic linkage with that catalysing the 4‐hydroxylation of debrisoquine?

Kahn¹,

Boobis²,

Brodie³

et al. 1985

Brit J Clinical Pharma

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“…Additionally, sarpogrelate or M-1 was tested as an inhibitor of bufuralol 19-hydroxylase (Boobis et al, 1985;Kronbach et al, 1987), metoprolol a-hydroxylase (Otton et al, 1988), and other CYP2D6-specific biotransformation pathways. Concentrations of bufuralol (5 mM) and metoprolol (20 mM) were used in this study.…”

Section: Methodsmentioning

confidence: 99%

Selective Inhibition of Cytochrome P450 2D6 by Sarpogrelate and Its Active Metabolite, M-1, in Human Liver Microsomes

et al. 2013

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The present study was performed to evaluate the in vitro inhibitory potential of sarpogrelate and its active metabolite, M-1, on the activities of nine human cytochrome (CYP) isoforms. Using a cocktail assay, the effects of sarpogrelate on nine CYP isoforms and M-1 were measured by specific marker reactions in human liver microsomes. Sarpogrelate potently and selectively inhibited CYP2D6-mediated dextromethorphan O-demethylation with an IC 50 (K i ) value of 3.05 mM (1.24 mM), in a competitive manner. M-1 also markedly inhibited CYP2D6 activity; its inhibitory effect with an IC 50 (K i ) value of 0.201 mM (0.120 mM) was more potent than that of sarpogrelate, and was similarly potent as quinidine (K i , 0.129 mM), a well-known typical CYP2D6 inhibitor. In addition, sarpogrelate and M-1 strongly inhibited both CYP2D6-catalyzed bufuralol 19-hydroxylation and metoprolol a-hydroxylation activities. However, sarpogrelate and M-1 showed no apparent inhibition of the other following eight CYPs: CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2E1, or CYP3A4/5. Upon 30-minute preincubation of human liver microsomes with sarpogrelate or M-1 in the presence of NADPH, no obvious shift in IC 50 was observed in terms of inhibition of the nine CYP activities, suggesting that sarpogrelate and M-1 are not time-dependent inactivators. Sarpogrelate strongly inhibited the activity of CYP2D6 at clinically relevant concentrations in human liver microsomes. These observations suggest that sarpogrelate could have an effect on the metabolic clearance of drugs possessing CYP2D6-catalyzed metabolism as a major clearance pathway, thereby eliciting pharmacokinetic drug-drug interactions.

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“…Microsomal protein content, with bovine serum albumin, fraction V, as standard (Lowry et al, 1951;Boobis et al, 1980b), debrisoquine 4-hydroxylase activity (Kahn et al, 1982;Boobis et al, 1983), at a substrate concentration of 0.2 mm, bufuralol 1 '-hydroxylase activity (Boobis et al, 1985) at a substrate concentration of 0.05 mm, and cytochrome P-450 content (Boobis et al, 1980b) were all determined as previously described. Aldrin epoxidase activity was assayed by a modification (Boobis & Davies, 1984) of the method of Wolff et al (1979) at a substrate concentration of 0.05 mm.…”

Section: Enzyme Assaysmentioning

confidence: 99%

Attempts to phenotype human liver samples in vitro for debrisoquine 4‐ hydroxylase activity.

Boobis¹,

Hampden²,

Murray³

et al. 1985

Brit J Clinical Pharma

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Twenty‐eight samples of human liver have been characterised for cytochrome P‐450 content, aldrin epoxidase, debrisoquine 4‐hydroxylase and bufuralol 1'‐hydroxylase activities. Evidence is presented here and elsewhere that bufuralol 1'‐hydroxylase and debrisoquine 4‐hydroxylase are activities catalysed by the same form of cytochrome P‐450 in man, and that this form is different from that catalysing the epoxidation of aldrin. Attempts to phenotype liver samples in vitro, in the absence of any metabolic data in vivo for debrisoquine 4‐hydroxylation status, met with limited success. A combination of enzyme assays will most probably be required in any such phenotyping of human liver samples.

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Genetic polymorphism in drug oxidation: In vitro studies of human debrisoquine 4-hydroxylase and bufuralol 1′-hydroxylase activities

Cited by 62 publications

References 8 publications

Phenacetin O‐deethylase: an activity of a cytochrome P‐450 showing genetic linkage with that catalysing the 4‐hydroxylation of debrisoquine?

Phenacetin O‐deethylase: an activity of a cytochrome P‐450 showing genetic linkage with that catalysing the 4‐hydroxylation of debrisoquine?

Selective Inhibition of Cytochrome P450 2D6 by Sarpogrelate and Its Active Metabolite, M-1, in Human Liver Microsomes

Attempts to phenotype human liver samples in vitro for debrisoquine 4‐ hydroxylase activity.

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