DrSteveMitchell

Summary

Stephen Mitchell B.Sc., B.Phil., Ph.D., D.Sc.

Research Interests

Polymorphic variability in human drug oxidation was first discovered at Imperial College (St. Mary''s) and is a well established area of expertise.

The primary focus of current research is the ''fish-odour syndrome'', a distressing complaint which causes the sufferer to emanate a pungent odour resembling that of rotten and decaying fish. Pharmacogenetic screening in a British population has established that the afflicted individuals have an impaired ability to N-oxidize trimethylamine and that this defect, which affects roughly 1 in 30,000, is inherited as an autosomal recessive trait. Such problems have also been shown to occur in other populations (Ecuadorian, Jordanian and New Guinean).

Collaborative studies have traced the molecular defect to an isozyme of flavin-monooxygenase (FMO3) and this obvious functional consequence of a genomic variant has stimulated world-wide interest in the previously neglected flavin-monooxygenase family of enzymes. Detection and elucidation of all of the genotype differences which give rise to dysfunctional FMO3 enzymes and ''fish odour syndrome'' will permit future pharmacogenomic screening of populations and also, with subsequent cloning and expression, enable the potential consequences of altered enzyme function for other substrates (drugs, food components, toxins, etc) to be understood.

For example, it has already been demonstrated, for the first time in humans, that the activity of FMO3, and especially that of variant forms, can be significantly influenced by fluctuating steroid hormone levels. The syndrome has attracted extensive media interest and the Department became the first UK centre for biochemical confirmation of the disorder and was instrumental in initiating and subsequently organising the ''First International Workshop on Fish-Odour Syndrome'' (at Bethesda. USA, 29-30/3/99) with unique joint funding from the National Institutes of Health (Office of Rare Diseases) and the Wellcome Trust. Following on from this success, a second ''Workshop on Trimethylaminuria'' has just been organised and it is hoped that this will become a continuing series.

Other anecdotal situations where groups of subjects exhibit apparently trivial differences in their handling of food components are under study in an attempt to increase the catchment area for potentially important biochemical/physiological differences which may have far greater ramifications in overall health and disease. Two such phenomenon are the production by some individuals of odorous urine after eating asparagus and red urine after beetroot ingestion. The asparagus phenomenon appears to be under ''simple'' genetic control and the offending chemicals have been identified. Beeturia appears dose-related with subjects having different thresholds, preliminary results suggesting differences in gastrointestinal absorption of beet pigments. Mechanistic implications are now under investigation.

Additional research interests include unravelling the anomalous properties of sulphoxide (and sulphone) containing compounds, when compared to their parent sulphide molecules. In particular, their unusual distribution around the body, transport via the lymphatic system and unexpected excretion within the bile. The potential of these findings in xenobiotic disposition and targeting are being studied. The influence of chirality on the disposition and fate of drugs usually prescribed as racemic mixtures are also being examined and interesting findings of stereoselective differences in metabolism and specific enantiomer interactions with metabolic enzymes will lead to a fuller appreciation of chiral drug mixtures and the hopefully safer prescribing. One such compound that we have recently investigated, levobupivacaine, has entered the US and EU market as the single enantiomer drug, ''Chirocaine''. The antimalaria agent, chloroquine, is presently under investigation.

Relevant Publications

Al-Waiz, M., Ayesh,R., Mitchell, S.C., Idle, J.R., Smith, R.L. (1987) Trimethylaminuria (Fish-Odour Syndrome): An inborn error of metabolism. Lancet, i, 634-635.

Ayesh, R., Mitchell, S.C., Zhang, A.Q. Smith R.L. (1993) The fish-odour syndrome; biochemical, familial and clinical aspects. Brit. Med. J., 307, 655-657.

Zhang, A.Q., Mitchell, S.C., Smith, R.L. (1996) Discontinuous distribution of N-oxidation of dietary-derived trimethylamine in a British population. Xenobiotica, 26, 957-961.

Mitchell, S.C., Zhang, A.Q., Barrett, T., Ayesh, R., Smith, R.L. (1997) Studies on the discontinuous N-oxidation of trimethylamine among Jordanian, Ecuadorian and New Guinean populations. Pharmacogenetics, 7, 45-50.

Ayesh, R., Mitchell, S.C., Smith. R.L. (1995) Dysfunctional N-oxidation of trimethylamine and the influence of testosterone treatment in man. Pharmacogenetics, 5, 244-246.

Zhang, A.Q., Mitchell, S.C., Smith R.L. (1996) Exacerbation of symptoms of fish-odour syndrome during menstruation. Lancet, 348, 1740-1741.

Mitchell, S.C. (1996) The Fish-Odour Syndrome. Perspec. Biol. Med., 39, 223-235.

Mitchell, S., Ayesh, R., Barrett, T, Smith, R. (1999) Trimethylamine and Foetor Hepaticus. Scand. J. Gastroenterol., 34, 524-528.

Mitchell, S.C. (1999) Trimethylaminuria: Susceptibility of heterozygotes. Lancet, 354, 2164-2165.

Mitchell, SC., Smith, R.L. (2001) Trimethylaminuria: the fish malodor syndrome. Drug Metab. Dispos., 29,517-521.

Mitchell, S.C., Waring, R.H., Land, D., Thorpe, W.V. (1987) Odorous urine following asparagus ingestion in man. Experientia, 43, 382-383.

Mitchell, S.C. (1996) Beeting a crimson retreat: Beeturia. Lancet, 347, 474-475.

Mitchell, S.C. (2001) Food Idiosyncrasies: Beetroot and asparagus. Drug Metab. Dispos., 29, 539-543.

Mitchell, S.C. (1996) (Ed.) Biological Interactions of Sulfur Compounds. Taylor & Francis, London.

Zhang, A.Q., Mitchell, S.C., Caldwell, J. (1998) The application of capillary gas chromatography - selective ion mass spectrometry for the separation, identification and quantification of phenolic bupivacaine metabolites from human urine. J. Pharm. Biomed. Anal. 17, 1139-1142.

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