Overview
Polymorphic variability in human drug oxidation was first discovered at Imperial College (St. Mary's) and is a well established area of expertise within the University. From these initial observations concerning cytochromes P450 the field of 'pharmacogenetics' has vastly expanded into the worldwide arena and has been shown to have profound ramifications for human health and disease aetiology as well as shaping thinking within the pharmaceutical industry.
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 problem, which affects roughly 1 in 30,000, is inherited as an autosomal recessive trait. Such conditions have also been shown to occur in other populations (Ecuadorian, Jordanian and New Guinean).
Collaborative studies have traced the molecular site to an isozyme of flavin-monooxygenase (FMO3) [the other major family of microsomal mono-oxygenases found in man] 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 (drug efficacy and toxicity, reaction to food components, 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) with unique joint funding from the National Institutes of Health (Office of Rare Diseases) and the Wellcome Trust. A second meeting has now been held with a third already in the planning stage and it is hoped that this will be destined to become a continuing series.
The role of phenylalanine 4-monoxygenase, a cytosolic enzyme, in classical endobiotic metabolism, and its genetic variants that underpin our understanding of phenylketonuria, are well known. This enzyme also appears to be responsible for the oxidation of sulphur-containing drugs, especially those employed as adjuncts in the treatment of glue ear and chronic obstructive airways disease. Variation in metabolism observed between individuals, with its consequent effects on pharmacokinetic profiles, may help to explain why such drugs are effective in some patients and not others. More fundamental is an emerging recognition that enzymes classically identified (and named) as being unmistakably involved in intermediary metabolism may also undertake xenobiotic and drug biotransformations.
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 and unappreciated consequences for 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.
The influence of specific chiral aspects in drug behaviour, exemplified by thalidomide, unusual metabolic behaviour and minor pathways of metabolism, are also under investigation.
For more information on the above and a general overview...
Polymorphic N-oxidation and Trimethylaminuria ('Fish odour Syndrome')
Mitchell,S.C., Smith R.L. (2010) A physiological role for flavin-containing monooxygenase (FMO3) in humans. Xenobiotica, 40, 301-305.
Mitchell, S.C. (2008) Flavin mono-oxygenase (FMO): The 'other' oxidase. Current Drug Metabolism, 9, 280-284.
Mitchell, S.C., Bollard, M.E. & Zhang, A. (2007) Short-chain aliphatic amines in human urine: a mathematical examination of metabolic interrelationships. Metabolism, 56, 19-23.
Cashman, J.R., Camp, K., Fakharzadeh, S.S., Fennessey, P.V., Hines, R.N., Mamer, O.V., Mitchell, S.C., Preti, G., Schlenk, D., Smith, R.L., Tjoa, S.S., Williams, D.E. & Yannicelli, S. (2003) Biochemical and clinical aspects of the human flavin-containing monooxygenase form 3 (FMO3) related to trimethylaminuria. Current Drug Metabolism, 4, 151-170.
Mitchell, S.C. & Smith, R.L. (2001) Trimethylaminuria: the fish malodor syndrome. Drug Metabolism and Disposition, 29, 517-521.
Mitchell, S.C. (1999) The fish-odour syndrome. Perspectives in Biology and Medicine, 39, 223-235.
Zhang, A.Q., Mitchell, S.C. & Smith, R.L. (1996) Exacerbation of symptoms of fish-odour syndrome during menstruation. Lancet, 348, 1740-1741.
Ayesh,R., Mitchell, S.C., Zhang, A..Q. & Smith, R.L. (1993) The fish-odour syndrome: biochemical, familial and clinical aspects. British Medical Journal, 307, 655-657.
Phenylalanine 4-monooxygense and sulphoxidation
Steventon, G.B. & Mitchell, S.C. (2009) Mouse recombinant phenylalanine monooxygenase and the S-oxygenation of thioether substrates. Journal of Biochemistry and Molecular Toxicology, 23, 119-124.
Steventon, G.B., Mitchell, S.C., Perez,B., Desviat, L.R. & Ugarte, M. (2009) The activity of phenylalanine hydroxylase with respect to the C-oxidation of phenylalanine and the S-oxidation of S-carboxymethy-L-cysteine. Molecular Genetics and Metabolism, 96, 27-31.
Boonyapiwat, B., Panaretou, B., Forbes, B., Mitchell, S.C. & Steventon, G.B. (2009) Human phenylalanine monooxygenase and thioether metabolism. Journal of Pharmacy and Pharmacology, 61, 63-67.
Patel, N.G., Iliadou, C., Boonyapiwat, B., Barlow, D.J., Forbes, B., Mitchell, S.C. & Steventon, G.B. (2008) Enzyme kinetic and molecular modelling studies of sulfur-containing substrates of phenylalanine 4-monooxygenase. Journal of Enzyme Inhibition and Medicinal Chemistry 23, 958-963.
Mitchell, S.C., Waring, R.H., Haley, C.S., Idle, J.R. & Smith, R.L. (1984) Genetic aspects of the polymodally distributed sulphoxidation of S-carboxymethyl-L-cysteine in man. British Journal of Clinical Pharmacology 18, 507-521.
Mitchell S.C. & Steventon G.B. (2012) S-carboxymethyl-L-cysteine. Drug Metabolism Reviews 44, 129-147.
Enzymology, intermediary metabolism and xeno-biotransformation
Antypa, A., Rebello, C., Biernacka, A., Krajewski, K., Cassam, J., Mitchell, S.C., Steventon, G.B. (2010) Post-translational activation of human phenylalanine 4-monooxygenase from an endobiotic to a xenobiotic enzyme by reactive oxygen and reactive nitrogen species. Xenobiotica, 40, 319-330.
Steventon, G.B., Mitchell, S.C. (2009) Phenylalanine 4-monooxygenase and the role of endobiotic metabolism enzymes in xenobiotic biotransformation. Expert Opinion in Drug Metabolism and Toxicology, 5, 1213-1221.
Mitchell, S.C. & Steventon, G.B. (2009) Foreign compounds and intermediary metabolism; Sulfoxidation bridges the divide. Current Drug Metabolism, 10, 220-226.
Steventon, G.B. & Mitchell, S.C. (2006) Non-classical drug metabolism enzymes. Letters in Drug Design and Discovery, 3, 404-412.
Mitchell, S.C. & Steventon, G.B. (2006) Drug metabolism and toxicity; Hijacking enzymes of intermediary metabolism. Current Topics in Toxicology, 3, 57-63.
Hague, D.E., Idle, J.R., Mitchell, S.C., Smith, R.L. (2011) Racemates revisited: Heterochiral assemblies and the example of DL-thalidomide. Xenobiotica 41, 837-843.
Mitchell SC, Waring RH, Smith RL. (2014) Curiosities in drug metabolism. Xenobiotica 44, early online.
Asparagus and Beetroot and Urinary Consequences
Mitchell, S.C. (2001) Food idiosyncrasies: Beetroot and asparagus. Drug Metabolism and Disposition, 29, 539-543.
Mitchell, S.C. (1996) Beeting a crimson retreat: Beeturia. Lancet, 347, 474-475.
Mitchell, S.C., Waring,R.H., Land,D. & Thorpe, W.V. (1987) Odorous urine following asparagus ingestion in man. Experientia, 43, 382-383.
Waring, R.H., Mitchell, S.C. & Fenwick, G .R. (1987 ) The chemical nature of the urinary odour produced by man after asparagus ingestion. Xenobiotica, 17, 1363-1371.
Mitchell S.C. (2013) Asparagus, urinary odor, and 1-2-dithiolane-4-carboxylic acid. Perspectives in Biology and Medicine 56, 314-315.
Mitchell, S.C. & Waring, R.H. (2014) Asparagusic acid. Phytochemistry, 97, 5-10
General Toxicology
Mitchell, S.C., Carmichael, P.L. & Waring, R.H. (2004) The three cornerstones of toxicology. Biologist, 51, 212-215.
'Molecules of Death' (2007) Imperial College Press. (Waring, R.H., Steventon, G.B. & Mitchell, S.C., Eds) 2nd edition. 430pp. [First edition, 2002]. S.C.Mitchell - 'Hydrofluoric acid' pp.119- 129; 'Phosphorus' pp 281-296.