Kinetics and specificity of guinea pig liver aldehyde oxidase and bovine milk xanthine oxidase towards substituted benzaldehydes.
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Molybdenum-containing enzymes, aldehyde oxidase and xanthine oxidase, are important in the oxidation of N-heterocyclic xenobiotics. However, the role of these enzymes in the oxidation of drug-derived aldehydes has not been established. The present investigation describes the interaction of eleven structurally related benzaldehydes with guinea pig liver aldehyde oxidase and bovine milk xanthine oxidase, since they have similar substrate specificity to human molybdenum hydroxylases. The compounds under test included mono-hydroxy and mono-methoxy benzaldehydes as well as 3,4-dihydroxy-, 3-hydroxy-4-methoxy-, 4-hydroxy-3-methoxy-, and 3,4-dimethoxy-benzaldehydes. In addition, various amines and catechols were tested with the molybdenum hydroxylases as inhibitors of benzaldehyde oxidation. The kinetic constants have shown that hydroxy-, and methoxy-benzaldehydes are excellent substrates for aldehyde oxidase (Km values 5×10-6 M to 1×10-5 M) with lower affinities for xanthine oxidase (Km values around 10-4 M). Therefore, aldehyde oxidase activity may be a significant factor in the oxidation of the aromatic aldehydes generated from amines and alkyl benzenes during drug metabolism. Compounds with a 3-methoxy group showed relatively high Vmax values with aldehyde oxidase, whereas the presence of a 3-hydroxy group resulted in minimal Vmax values or no reaction. In addition, amines acted as weak inhibitors, whereas catechols had a more pronounced inhibitory effect on the aldehyde oxidase activity. It is therefore possible that aldehyde oxidase may be critical in the oxidation of the analogous phenylacetaldehydes derived from dopamine and noradrenaline.
- Beedham C. (1985) Molybdenum hydroxylases as drug-metabolizing enzymes. Drug Metab Rev.; 16: 119-56.
- Beedham C. (1987) Molybdenum hydroxylases: biological distribution and substrate-inhibitor specificity. Prog Med Chem.; 24: 85-127.
- Beedham C, Bruce SE, Critchley DJ, Al-Tayib Y, Rance DJ. (1987a) Species variation in hepatic aldehyde oxidase activity. Eur J Drug Metab Pharmacokinet.; 12: 307-10.
- Beedham C, Bruce SE, Rance DJ. (1987b) Tissue distribution of the molybdenum hydroxylases, aldehyde oxidase and xanthine oxidase, in male and female guinea pigs. Eur J Drug Metab Pharmacokinet.; 12: 303-6.
- Beedham C, Bruce SE, Critchley DJ, Rance DJ. (1990) 1-Substituted phthalazines as probes of the substrate-binding site of mammalian molybdenum hydroxylases. Biochem Pharmacol.; 39: 1213-21.
- Beedham C, Critchley DJP, Rance DJ. (1995a) Substrate specificity of human liver aldehyde oxidase toward substituted quinazolines and phthalazines: a comparison with hepatic enzyme from guinea pig, rabbit and baboon. Arch Biochem Biophys.; 319: 481-90.
- Beedham C, Peet CF, Panoutsopoulos GI, Carter H, Smith JA. (1995b) Role of aldehyde oxidase in biogenic amine metabolism. Prog Brain Res.; 106: 345-53.
- Booth VH. (1938) The specificity of xanthine oxidase. Biochem J.; 32: 494-502.
- Bradford MM. (1976) A rapid and sensitive method for the quantification of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem.; 72: 248-54.
- Bruder G, Heid H, Jarasch ED, Keenan TW, Mather IH. (1982) Characteristics of membrane-bound and soluble forms of xanthine oxidase from milk and endothelial cells of capillaries. Biochim Biophys Acta.; 701: 357-69.
- Coughlan, MP. (1980) In Molybdenum and Molybdenum Containing Enzymes. Coughlan MP, ed. Pergamon Press, Oxford.
- Coughlan MP, Ni Fhaolain I. (1979) On the sites of interaction of oxidizing substrates with molybdenum iron/sulphur flavin hydroxylases. Proc R Ir Acad B.; 79: 169-75.
- Critchley DJP. (1989) In Diazanaphthalenes as Probes of Molybdenum Hydroxylase Activity. PhD Thesis, University of Bradford, Bradford, UK.
- Critchley DJ, Rance DJ, Beedham C. (1992) Subcellular localization of guinea pig hepatic molybdenum hydroxylases. Biochem Biophys Res Commun.; 185: 54-9.
- Dellarco VL. (1988) A mutagenicity assessment of acetaldehyde. Mutat Res.; 195: 1-20.
- Feron VJ, Til HP, de Vrijer F, Woutersen RA, Cassee FR, van Bladeren PJ. (1991) Aldehydes: occurrence, carcinogenic potential, mechanism of action and risk assessment. Mutat Res.; 259: 363-85.
- Goodall McC, Alton H. (1968) Metabolism of 3-hydroxytyramine (dopamine) in human subjects. Biochem Pharmacol.; 17: 905-14.
- Gordon AH, Green DE, Subrahmanyan V. (1940) Liver aldehyde oxidase. Biochem J.; 34: 764-74.
- Hazen SL, Hsu FF, d'Avignon A, Heinecke JW. (1998) Human neutrophils employ myeloperoxidase to convert α-amino acids to a battery of reactive aldehydes: a pathway for aldehyde generation at sites of inflammation. Biochemistry.; 37: 6864-73.
- Johns DG. (1967) Human liver aldehyde oxidase: Differential inhibition of oxidation of charged and uncharged substrates. J Clin Invest.; 46: 1492-505.
- Johnson C, Stubley-Beedham C, Stell JGP. (1985) Hydralazine: A potent inhibitor of aldehyde oxidase activity in vitro and in vivo. Biochem Pharmacol.; 34: 4251-6.
- Krenitsky TA, Neil SM, Elion GB, Hitchings GH. (1972) A comparison of the specificities of xanthine oxidase and aldehyde oxidase. Arch Biochem Biophys.; 150: 585-99.
- Krenitsky TA, Spector T, Hall WW. (1986) Xanthine oxidase from human liver: purification and characterization. Arch Biochem Biophys.; 247: 108-19.
- Lindahl R. (1992) Aldehyde dehydrogenases and their role in carcinogenesis. Crit Rev Biochem Mol Biol.; 27: 283-335.
- Ma TH, Harris MM. (1988) Review of the genotoxicity of formaldehyde. Mutat Res.; 196: 37-59.
- Modi VV, Owen EC, Proudfoot R. (1959) Species differences in the occurrence of xanthine oxidase in milk. Proc Nutr Soc.; 18: i.
- Morpeth FF. (1983) Studies on the specificity toward aldehyde substrates and steady-state kinetics of xanthine oxidase. Biochim Biophys Acta.; 744: 328-34.
- Panoutsopoulos GI. (1994) In Hepatic Oxidation of Aromatic Aldehydes. PhD Thesis, University of Bradford, Bradford, UK.
- Pelsy G, Klibanov AM. (1983) Remarkable positional (regio)specificity of xanthine oxidase and some dehydrogenases in the reactions with substituted benzaldehydes. Biochim Biophys Acta.; 742: 352-7.
- Rajagopalan KV, Handler P. (1964) Hepatic aldehyde oxidase: The substrate-binding site. J Biol Chem.; 239: 2027-35.
- Sasaki K, Hosoya R, Wang YM, Raulston GL. (1983) Formation and disposition of 7-hydroxymethotrexate in rabbits. Biochem Pharmacol.; 32: 503-7.
- Smith RF, Otremba ED. (1962) The preparation and properties of some 1,2-dihydroxyphthalazine derivatives. J Org Chem.; 27: 879-82.
- Spector T, Hall WW, Krenitsky TA. (1986) Human and bovine xanthine oxidases: Inhibition studies with oxipurinol. Biochem Pharmacol.; 35: 3109-14.
- Stubley C, Stell JGP. (1980) Investigation of the substrate-binding site of aldehyde oxidase. J Pharm Pharmac.; 32: 51P.
- Taylor SM, Stubley-Beedham C, Stell JGP. (1984) Simultaneous formation of 2- and 4-quinolones from quinolinium cations catalysed by aldehyde oxidase. Biochem J.; 220: 67-74.
- Washio K, Makaya O, Sasaki H, Nishida K, Nakamura J, Shibasaki J. (1993) A new aspect of tolbutamide metabolism in the rabbit: the role of 1-butyl-3-(p-formylphenyl) sulphonylurea. J Pharm Pharmacol.; 45: 231-3.
- Wilkof CA, Korus RA, Crawford DL, Pometto III AL. (1984) Enzymic oxidation of aromatic aldehydes. Biotechnol Bioeng Symp.; 14: 419-23.
- Williams CM, Bubuscio AA, Watson R. (1960) In vivo alteration of the pathways of dopamine metabolism. Am J Physiol.; 199: 722-6.
- Wurzinger KH, Hartenstein R. (1974) Phylogeny and correlations of aldehyde oxidase, xanthine oxidase, xanthine dehydrogenase and peroxidase in animal tissues. Comp Biochem Physiol.; 49B: 171-85.
- Xia M, Dempski R, Hille R. (1999) The reductive half-reaction of xanthine oxidase. J Biol Chem.; 274: 3323-30.
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