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Genetically Determined Variability in Acetylation and Oxidation

Therapeutic Implications

Drugs volume 29, pages 342–375 (1985)Cite this article

Summary

The clinical significance of two separate genetic polymorphisms which alter drug metabolism, acetylation and oxidation is discussed, and methods of phenotyping for both acetylator and polymorphic oxidation status are reviewed. Particular reference is made to the dapsone method, which provides a simple means of distinguishing fast and slow — and possibly intermediate — acetylators, and to the sparteine method which allows a clear separation of oxidation phenotypes.

Although acetylation polymorphism has been known for some time, definite indications for phenotyping are few. It is doubtful whether acetylator phenotype makes a significant difference to the outcome in most isoniazid treatment regimens, and peripheral neuropathy from isoniazid in slow acetylators is easily overcome by pyridoxine administration. However, in comparison with rapid acetylators, slow acetylators receiving isoniazid have an increased susceptibility to Phenytoin toxicity, and perhaps also to carbamazepine toxicity. It is also possible that rapid acetylators receiving isoniazid attain higher serum fluoride concentrations from enflurane and similar anaesthetics than do similarly treated slow acetylators. Thus, when drug interactions of these types are suspected, phenotyping for acetylator status may be advisable.

If routine monitoring of serum procainamide and N-acetylprocainamide concentrations is practised, phenotyping of subjects prior to therapy with these agents should not be necessary. Although acetylator phenotype influences serum concentrations of hydralazine, when this drug is given in combination with other drugs acetylator phenotype has not been shown to influence the therapeutic response. Slow acetylator phenotype along with female gender and the presence of HLA-DR antigens appear to be risk factors in the development of hydralazine-induced systemic lupus erythematosus (SLE). Determination of acetylator phenotype may therefore help determine susceptibility to this adverse reaction. In the case of sulphasalazine, adult slow acetylators require a lower daily dose of the drug than fast acetylators in order to maintain ulcerative colitis in remission without significant side effects. It is therefore advisable to determine acetylator phenotype prior to sulphasalazine therapy.

Work on the association of acetylation polymorphism with various disease states is also reviewed. It is possible that a higher incidence of bladder cancer is associated with slow acetylation phenotype — especially in individuals exposed to high levels of arylamines. The question as to whether idiopathic SLE is more common in slow acetylators remains unresolved. There appears to be no difference between fast and slow acetylators in susceptibility to generalised rheumatoid arthritis, but slow acetylators may be more common amongst rheumatoid arthritis patients with Sjögren’s syndrome than amongst rheumatoid patients without this syndrome. An excess of slow acetylators has been noted in patients with Gilbert’s syndrome, but the clinical significance of this is uncertain.

Polymorphic oxidation, characterised by the impaired ability of between 5 and 10% of the population to oxidise debrisoquine or sparteine, has been known for a much shorter time than has polymorphic acetylation, and work on the clinical significance of this polymorphism is far from complete. A number of β-adrenoceptor blocking drugs, e.g. metoprolol, have been shown to share the same oxidation pathway as debrisoquine and sparteine, but so far this has not been demonstrated to be of clinical importance. However, the incidence of peripheral neuropathy after perhexiline has been shown to be significantly increased in poor oxidisers. Determination of oxidation status prior to use of this drug could help to determine dosage and to control its neurotoxicity.

The kinetics of certain tricyclic antidepressants, including nortriptyline and desipramine, are related to oxidation status but the full clinical significance of this is not known. The oxidation of Phenytoin is only partly affected by the form of cytochrome P-450 involved in sparteine and debrisoquine oxidation. As measurement of Phenytoin blood concentrations provides a guide to dosage, phenotyping with debrisoquine or sparteine is not justified.

Encainide requires oxidation in the body for it to have significant antiarrhythmic activity, and reduced activity in poor oxidisers of debrisoquine has been noted. Prior phenotyping for oxidation status may therefore be advisable before treatment with this drug. Several other drugs, not now widely used clinically, have also been shown to share the debrisoquine/sparteine oxidation pathway (e.g. guanoxan, phenacetin, metiamide, phenformin, and methoxyamphetamine) and this has implications with regard to the toxicity of these drugs.

Genetic polymorphisms in drug metabolism should be allowed for in the development and monitoring of new drugs. Other oxidation pathways not associated with debrisoquine or sparteine (such as that of tolbutamide, mephenytoin and S-carboxymethyl-L-cysteine) may also involve genetic polymorphisms. Clinicians and others in the health-care team, when confronted with an adverse drug reaction, should bear in mind the possible influence of genetic polymorphism.

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  1. Department of Pharmacology, University of Otago Medical School, P.O. Box 913, Dunedin, New Zealand

    David W. J. Clark

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Clark, D.W.J. Genetically Determined Variability in Acetylation and Oxidation. Drugs 29, 342–375 (1985). https://doi.org/10.2165/00003495-198529040-00003

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Keywords

  • Systemic Lupus Erythematosus
  • Isoniazid
  • Hydralazine
  • Dapsone
  • Poor Metabolisers