The specificity of inhibition of debrisoquine 4-hydroxylase activity by quinidine and quinine in the rat is the inverse of that in man.

@article{Kobayashi1989TheSO,
  title={The specificity of inhibition of debrisoquine 4-hydroxylase activity by quinidine and quinine in the rat is the inverse of that in man.},
  author={S. Kobayashi and Stephen Murray and David Watson and Dorothea Sesardic and Donald S. Davies and Alan R. Boobis},
  journal={Biochemical pharmacology},
  year={1989},
  volume={38 17},
  pages={
          2795-9
        }
}
4-Hydroxylation of debrisoquine by human CYP1A1 and its inhibition by quinidine and quinine.
TLDR
Findings have significant implications for the conduct of in vitro drug metabolism inhibition studies and underscore the fallacy of "specific chemical inhibitors" of a supergene family of enzymes that have overlapping substrate specificities.
Quinine is a more potent inhibitor than quinidine in rat of the oxidative metabolic routes of methoxyphenamine which involve debrisoquine 4-hydroxylase.
TLDR
As quinidine is a more potent inhibitor than quinine of debrisoquine 4-hydroxylase in man, the rat should be used only with full realization of its limitations when investigating substrates metabolized by this isoenzyme.
The In vitro hepatic metabolism of quinine in mice, rats and dogs: comparison with human liver microsomes.
TLDR
3-hydroxyquinine is a main metabolite of quinine and that CYP3A/Cyp3a is a principal isoform involved in this metabolic pathway in the respective (rat, dog and human/mouse) species tested.
Major role of the CYP2C isozymes in deamination of amphetamine and benzphetamine: evidence for the quinidine-specific inhibition of the reactions catalysed by rabbit enzyme.
TLDR
The results strongly support the notion that the CYP2C isozymes play a major role in the deamination of both AP and BZP, but not for N-debenzylation of BzP in rat.
Inactivation of rat cytochrome P450 2D enzyme by a further metabolite of 4-hydroxypropranolol, the major and active metabolite of propranolol.
TLDR
Rat liver microsomal PL 5- and 7-hydroxylases by 4-OH-PL was blocked efficiently by co-incubation with quinine, a typical inhibitor of rat CYP2D enzyme(s), or to a lesser extent by BTL.
Involvement of CYP2D1 in the metabolism of carteolol by male rat liver microsomes.
TLDR
The results suggest that carteolol is metabolized to 8-hydroxylation of cartaolol by CYP2D1, a beta-adrenoceptor blocking drug, and has a lower affinity for CYP1D1 compared with these other beta- adreno receptor blocking drugs.
Inhibition of human CYP1A2 activity in vitro by methylxanthines: potent competitive inhibition by 8-phenyltheophylline
TLDR
The potency and specificity of 8-phenyltheophylline as an inhibitor of human hepatic CYP1A2 indicate that the compound may be useful as a chemical inhibitor of this enzyme for further in vitro studies.
An in vitro study on the metabolism and possible drug interactions of rokitamycin, a macrolide antibiotic, using human liver microsomes.
TLDR
This in vitro study was designed to identify the enzyme(s) involved in the two major metabolic pathways of rokitamycin and to assess possible drug interactions using human liver microsomes and it was concluded that the formations of LMA7 from rokit amycin and of LMV from L MA7 are catalyzed mainly by human esterase enzyme.
Role of specific cytochrome P450 enzymes in the N-oxidation of the antiarrhythmic agent mexiletine
TLDR
It is demonstrated that CYP1A2 is a major human cytochrome P450 enzyme involved in the formation of N -hydroxymexiletine, however, other cyto Chrome P450 enzymes (CYP2E1 and CYP2B6) also appear to play a role in the N-oxidation of this drug.
Selective involvement of cytochrome P450 2D subfamily in in vivo 4-hydroxylation of amphetamine in rat.
TLDR
The studies substantiate that 4-hydroxylation of amphetamine is selectively performed by the P450 2D subfamily in the rat and show that primaquine was shown to be an inhibitor of 2D activity.
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References

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Quinidine and the identification of drugs whose elimination is impaired in subjects classified as poor metabolizers of debrisoquine.
TLDR
The effects of quinidine at a dose of only 50 mg, on the metabolism of a new drug in EM subjects may prove a useful method of assessing the contribution of the debrisoquine 4-hydroxylase isozyme to the elimination of the drug tested.
Oxidation of quinidine by human liver cytochrome P-450.
TLDR
The anti-arrhythmic quinidine has been reported to be a competitive inhibitor of the catalytic activities of human liver P-450DB, including sparteine delta 2-oxidation and bufuralol 1'-hydroxylation, and the observation that submicromolar concentrations are strongly inhibitory is confirmed, consonant with in vivo observations.
Substrate specificity of the form of cytochrome P-450 catalyzing the 4-hydroxylation of debrisoquine in man.
TLDR
It is concluded that debrisoquine 4-hydroxylase is a specific form of cytochrome P-450 with a well-defined substrate specificity and it should be possible to identify compounds that might be subject to an oxidation polymorphism prior to the exposure of any subjects to the compound.
Assay and characterisation of debrisoquine 4-hydroxylase activity of microsomal fractions of human liver.
TLDR
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, which was associated with a decrease in enzyme activity.
Sex and strain differences in hepatic debrisoquine 4-hydroxylase activity of the rat.
TLDR
The DA rat might provide a suitable model in which to predict which substrates might show impaired oxidation in the poor metabolizer phenotype, but studies on the molecular mechanism of the polymorphism in this strain would appear to have doubtful validity for the polymorphisms in man.
Characterization of a human liver cytochrome P-450 involved in the oxidation of debrisoquine and other drugs by using antibodies raised to the analogous rat enzyme.
TLDR
Antibodies prepared to a cytochrome P-450 shown to be responsible for debrisoquine 4-hydroxylation in rats were found to inhibit the oxidation ofbrisoquine and sparteine, encainide, and propranolol, three other drugs suggested to be associated with this phenotype, in human liver microsomes.
Attempts to phenotype human liver samples in vitro for debrisoquine 4-hydroxylase activity.
TLDR
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, and a combination of enzyme assays will most probably be required in any such phenotyping of human liver samples.
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