Abstract
Drug and foreign compound biotransformations are mediated by a group of enzymes known collectively as the ‘drug-metabolizing enzymes’. These include the microsomal mixed function mono-oxygenases, commonly referred to as the cytochrome P-450s but also several non-cytochrome P-450 enzymes including the cytosolic alcohol dehydrogenase and the microsomal flavin-containing mono-oxygenase, otherwise known as Ziegler’s enzyme. Although such enzymes mediate the oxidation of xenobiotic compounds, many of them also have a known physiological role. Their activity is associated largely with the liver, however their presence has also been demonstrated in other tissues including lung, kidney and intestine. Furthermore, the enzymes of the gut flora are also known to be important mediators of the metabolism of certain xenobiotics.
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References
Al-Waiz, M. (1988) ‘Genetic, polymorphism of trimethylamine N-oxidation in man and its relationship to the fish-odour syndrome’. Ph.D. thesis. London University, pp.172–3.
Al-Waiz, M., Ayesh, R., Mitchell, S.C. et al. (1987a) Disclosure of the metabolic retroversion of trimethylamine N-oxide in humans. Clin. Pharmacol. Ther., 42, 602–12.
Al-Waiz, M., Mitchell, S.C, Idle, J.R. and Smith, R.L. (1987b) The metabolism of 14C-labelled trimethylamine and its N-oxidation in man. Xenobiotica, 17, 551–8.
Al-Waiz, M., Ayesh, R., Mitchell, S.C. et al. (1987c) A genetic polymorphism of the N-oxidation of trimethylamine in humans. Clin. Pharmacol. Ther., 42, 588–94
Al-Waiz, M., Ayesh, R., Mitchell, S.C. et al. (1987d) The relative importance of N oxidation and N-demethylation in the metabolism of trimethylamine in man. Toxicology, 43, 117–21.
Al-Waiz, M., Ayesh, R., Mitchell, S.C. et al. (1988) Trimethylaminuria(2018Fish-odour syndrome’): a study of an affected family. Clinical Science, 74, 231–6.
Al-Waiz, M., Ayesh, R., Mitchell, S.C. et al. (1989) Trimethylaminuria: the detection of carriers using a trimethyalmine load test. J. Inherited Metab. Dis., 12, 80–85.
Arbuthnot, J. (1735) in An Essay Concerning the Nature of Ailments, (3rd ed), J. Tonson, London, pp. 82–3.
Ayesh, R., Al-Waiz, M., Crothers, M. J. et al. (1988) Deficient nicotine N-oxidation in two sisters with trimethylaminuria. Br. J. Clin. Pharmacol., 25, 664.
Ayesh, R., Al-Waiz, M., McBurney, A. et al. (1989) Variable metabolism of pinacidil: lack of correlation with debrisoquine and trimethylamine C— and N-oxidative polymorphisms. Br. J. Clin. Pharmacol., 27, 423–8.
Baker, J.R. and Chaykin, S. (1960) The biosynthesis of trimethylamine N-oxide. Biochim. Biophys. Acta, 41, 548–50.
Baker, J.R. and Chaykin, S. (1962) The biosynthesis of trimethylamine N-oxide. J. Biol. Chem., 237, 1309–13.
Blumenthal, I., Lealman, G.T. and Franklyn, P.P. (1980) Fracture of femur, fish odour and copper deficiency in a preterm infant. Arch. Dis. Child., 55, 229–31.
Brand, J.M. and Galask, R.P. (1986) Trimethylamine: the substance mainly responsible for the fishy odour often associated with bacterial vaginosis. Obstet. Gynaecol., 68, 682–5.
Brewster, M.A. and Schedewie, H. (1983) Trimethylaminuria. Ann. Clin. Lab. Sci., 13,20–4
Cholerton, S., Ayesh, R., Idle, J.R. and Smith, R.L. (1988) The pre-eminence of nicotine N-oxidation and its diminution after carbimazole administration. Br. J. Clin. Pharmacol., 26, P652.
Cholerton, S., Ayesh, R., Robinson, H. et al. (1989) Secondary trimethylaminurias: effect of liver disease on the N-oxidation of trimethylamine. Prog. Pharmacol. Clin. Pharmacol., in press.
Damani, L.A., Pool, W.F., Crooks, P.A. et al. (1988) Stereoelectivity in the N-oxidation of nicotine isomers by flavin-containing monooxygenase. Mol. Pharmacol., 33,702–5.
Danks, D.M., Hammond, J., Schlesinger, P. et al. (1976) Trimethylaminuria: diet does not always control the fishy odour. N. Engl. J. Med., 295, 962.
De La Huerga, J. and Popper, M. (1951) Urinary excretion of choline metabolites following choline administration in normals and patients with hepatobiliary diseases. J. Clin. Invest., 30, 364–70.
Dessaignes, M. (1856) Trimethylamin aus menschenharn. Justis Liebigs Annalen der Chemie, 100, 218.
Drayer, D.E. and Reidenberg, M.M. (1977) Clinical consequences of polymorphic acetylation of basic drugs. Clin. Pharmacol. Ther. 22,251–8.
Dunstan, W.R. and Goulding, E. (1899) The action of alkyl haloids on hydroxylamine. Formation of substituted hydroxylamines and oxamines. J. Chem. Soc. (Lond.), 75, 792–807.
Dyer, F.E. and Wood, A.J. (1947) Action of enterobacteriaceae on choline and related compounds. J. Fish. Res. Bd Can., 7, 17–21.
Dyer, D.J. (1952) Amines in fish muscle. VI. Trimethylamine oxide content of fish and marine vertebrates. J. Fish. Res. Bd Can., 8, 314–24.
Eichelbaum, M., Baur, M.P. and Dengler, H.J. (1987) Chromosomal assignment of human cytochrome P-450 (debrisoquine/sparteine type) to chromosome 22. Br. J. Clin. Pharmacol., 23, 455–8.
Eichelbaum, M., Spannbrucker, N., Steincke, B. and Dengler, H.J. (1979) Defective N-oxidation of sparteine in man: a new pharmacogenetic defect. Eur. J. Clin. Pharmacol., 16, 183–7.
Etienne, P., Gauther, S., Johnson, G. et al. (1978) Clinical effects of choline in Alzheimer’s disease. Lancet, i, 508–9.
Evans, D.A.P., Harmer, D., Downtham, D.Y. et al. (1983) The genetic control of sparteine and debrisoquine metabolism in man with new methods of analyzing bimodal distribution. J. Med. Genet. 20, 321–9.
Fenwick, G.T., Heaney, R.K. and Mullin, J.W. (1983a) Glucosinolates and their breakdown products in food and food plants. CRC Crit. Rev. Food, Sci. Nutri. 18, 123–201.
Fenwick, G.R., Butler, E.J. and Brewster, M.A. (1983b) Are Brassica vegetables aggravating factors in trimethylaminuria? Lancet, i, 916.
Goedde, G.S. and Altland, K. (1971) Suxamethonium sensitivity. Ann. NY Acad. Sci., 179, 666–70.
Gonzalez, F.G., Skoda, R.C., Kimura, S. et al. (1988) Characterization of the common genetic defect in humans deficient in debrisoquine metabolism. Nature, 331,442–6.
Growden, J.H., Cohen, E.L. and Wurtmann, R.J. (1977) Huntington’s disease: clinical and chemical effects of choline administration. Ann. Neurol., 1, 418–22.
Harris, H. (1980) in The Principles of Human Biochemical Genetics (4th edn), North Holland, Amsterdam.
Higgins, T., Chagkin, S., Hammond, K.B. and Humbert, J.R. (1972) Trimethylamine N-oxide synthesis; human variant. Biochem. Med., 6, 392–6.
Hlavica, P. and Kehl, M. (1977) Studies on the mechanism of hepatic microsomal N-oxide formation. The role of cytochrome P-450 and mixed-function amine oxidase in the N-oxidation of N,N-dimethylaniline. Biochem. J., 164, 487–96.
Humbert, J.R., Hammond, K.B., Hathaway, W.E. et al. (1970) Trimethylaminuria: the fish-odour syndrome. Lancet, i, 770–1.
Johnson, G.B. (1973) Importance of substrate variability to enzyme polymorphism. Nature, 243, 151–3.
Johnson, G.B. (1974) Enzyme polymorphism and metabolism. Science, 184, 28–37.
Kadlubar, F.F., Miller, J.A. and Miller, E.C. (1976) Microsomal N-oxidation of the hepatocarcinogen N-methyl-4-aminoazobenzene and the reactivity of N-hydroxy-N-methyl-4-aminoazobenzene. Cancer Res. 36, 1196–206.
Lee, C.W.G., Tu, J.S., Turner, B.R. and Murphy, K.E. (1976) Trimethylaminuria: fishy odours in children. N. Engl. J. Med., 295, 937–8.
Lintzel, W. (1934) Trimethyloxyd. Menschlichen Harn. Klin. Wochenschr., 13,304–5.
Love, R.M. (1980) in The Chemical Biology of Fishes, Academic Press, London, pp. 458–9.
Mahgoub, A., Idle, J.R., Dring, L.G. et al. (1977) Polymorphic hydroxylation of debrisoquine in man. Lancet, ii, 484–6.
Marks, R., Graves, M.W., Prottey, C. and Hartop, P.J. (1977) Trimethylaminuria: the use of choline as an aid to diagnosis. Br. J. Dermatol., 96, 399–402.
Marks, R., Dudley, F. and Wan, A. (1978) Trimethylamine metabolism in liver disease. Lancet, i, 1106–7.
McManus, M.E., Stupans, J., Burgers, W. et al. (1987) Flavin-containing monooxygenase activity in human liver microsomes. Drug Metab. Dispos., 15, 256–61.
Mitchell, M.E. (1978) Carnitine metabolism in human subjects. I. Normal metabolism. Am. J. Clin. Nutr. 31, 293–306.
Mitchell, S.C, Waring, R.H., Haley, C.S. et al. (1984) Genetic aspects of the polymodally distributed sulphoxidation of S-carboxymethyl-L-cysteine in man. Br. J. Clin. Pharmacol., 18, 507–21.
Norris, E.R. and Benoit, G.J. (1945) Studies on trimethylamine oxide. I Occurrence of trimethylamine oxide in marine organisms. J. Biol. Chem., 158, 433–8.
Oginsky, E.L., Stein, A.E. and Greer, M.A. (1965) Myrosinase activity in bacteria as demonstrated by the conversion of progoitrin to goitrin. Proc. Soc. Exp. Biol. Med., 119,360–4
Pearson, A.W., Butler, E.J., Curtis, R.F. et al. (1979) Effects of rapeseed meal on trimethylamine metabolism in the domestic fowl in relation to egg taint. J. Sci. Food Agric., 30, 799–804.
Pearson, A.E., Fenwick, G.R., Greenwood, N.M. and Butler, E.J. (1980) The effects of goitrogens on the oxidation of trimethylamine in the domestic fowl (Galius domestical). Comp. Biochem. Biophys., 67A, 397–401.
Pearson, A.W., Greenwood, N.M., Butler, E.J. and Fenwick, G.R. (1981) The inhibition of trimethylamine oxidation in the domestic fowl (Gallus domesticus). Comp. Biochem. Biophys., 69C, 207–12.
Prentiss, P.G., Rosen, H., Brown, N. et al. (1961) The metabolism of choline in the germ free rat. Arch. Biochem. Biophys., 94, 424–9.
Ronald, O.A. and Jakobson, F. (1947) Trimethylamine oxide in marine products. J. Soc. Chem. Ind., 66, 160–6.
Rothschild, J.C. and Hansen, R.C. (1985) Fish odour syndrome: trimethylaminuria with milk a chief dietary factor. Pediatr. Dermatol., 3, 38–39c.
Ruocco, V., Florio, M., Grimaldi Filioli, F. et al. (1989) An unusual case of trimethylaminuria. Br. J. Dermatol., 120, 459–61.
Saborin, P.J. and Hodgson, E. (1984) Characterization of purified microsomal FAD-containing monooxygenase from mouse and pig liver. Chem. Biol. Interact., 51, 125–39.
Shelley, E.D. and Shelley, W.B. (1984) The fish-odour syndrome, trimethylaminuria. J. Am. Med. Assoc., 251, 253–5.
Shewan, J.M. (1951) The chemistry and metabolism of the nitrogen extractives of fish. Biochem. Soc. Symp., 6, 28–48.
Simenhoff, M.L., Burke, J.F., Sankkonen, J.J. et al. (1977) Biochemical profile of uraemic breath. N. Engl. J. Med., 297, 132–5.
Spellacy, E., Watts, R.W.E. and Goolamali, S.K. (1979) Trimethylaminuria. J. Inherited Metab. Dis., 2, 85–8.
Suwa, A. (1909) Untersuchungen uber die organextrakte der selachier. I. Die muskelextraktstoffe des dornhaies. Arch. Ges. Physiol., 128, 421–6.
Todd, A.W. (1979) Psychological problems as the major complication of an adolescent with trimethylaminuria. J. Pediatr., 94, 936–7.
Tver, D.F. and Russell, P. (1981) in Nutrition and Health Encyclopaedia, Von Nostrand Rheinhold, New York, p. 100.
Tynes, R.E. and Hodgson, E. (1985) Catalytic activity and substrate specificity of the flavin-containing monooxygenase in microsomal systems: characterization of the hepatic, pulmonary and renal enzymes of the mouse, rabbit and rat. Arch. Biochem. Biophys., 240, 77–93.
Tynes, R.E., Sabourin, P.J. and Hodgson, E. (1985) Identification of distinct hepatic and pulmonary forms of microsomal flavin-containing monooxygenase in the mouse and rabbit. Biochem. Biophys. Res. Commun., 126, 1069–75.
Vogel, F. (1959) Moderne Probleme der Humangenetik. Ergeb. Inn. Med. Kinderheilk., 12,52–125.
Willey, G.R. (1985) Trimethylamine — a pungent experience. Educ. Chem., 22, 178–81.
Williams, D.E., Hale, S.E., Meurhoff, A.S. and Masters, B.B.S. (1985) Rabbit lung flavin-containing monooxygenase. Purification, characterization and induction during pregnancy. Mol. Pharmacol., 28, 381–90.
Wills, M.R. and Savory, J. (1981) Biochemistry of renal failure. Annal. Clin. Lab. Sci., 11,292–9.
Wranne, L. (1956) Urinary excretion of trimethylamine and trimethylamine N-oxide following trimethylamine administration to normal and patients with liver disease. Acta Med. Scand., 153, 433–41.
Zeisel, S.H. (1981) Dietary choline: biochemistry, physiology and pharmacology. Ann. Rev. Nutr., I, 95–121.
Ziegler, D.M. (1980) Microsomal flavin-containing monooxygenase: oxygenation of nucleophilic nitrogen and sulphur compounds, in Enzymatic Basis of Detoxification (ed. W.B. Jakoby), Academic Press, New York, pp. 201–27.
Ziegler, D.M. (1985) Molecular basis for N-oxygenation of sec- and tert-amines, in Biological Oxidation of Nitrogen in Organic Molecules — Chemistry, Toxicology and Pharmacology (eds J.W. Gorrod and L.A. Damani), Ellis Horwood, Chichester, pp. 43–52.
Ziegler, D.M. and Mitchell, C.H. (1972) Microsomal oxidase. IV Properties of a mixed function amine oxidase isolated from pig liver microsomes. Arch. Biochem. Biophys., 150, 116–25.
Ziegler, D.M. and Poulsen, L.L. (1977) Protein disulphide bond synthesis: a possible intracellular mechanism, Trends in Biochemical Sciences, 2, 79–81.
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Cholerton, S., Smith, R.L. (1991). Human pharmacogenetics of nitrogen oxidations. In: Hlavica, P., Damani, L.A. (eds) N-Oxidation of Drugs. Springer, Dordrecht. https://doi.org/10.1007/978-94-011-3112-4_7
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DOI: https://doi.org/10.1007/978-94-011-3112-4_7
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