Abstract
Phosphorothioate compounds are widely used in agriculture and public health for the control of unwanted pests. The phosphorothioate parathion was metabolised to the toxic metabolite paraoxon (0.038–0.683 nmol/min per mg protein) and p-nitrophenol (0.023–2.10 nmol/min per mg protein) by human liver microsomes (n=27) in an NADPH-dependent reaction. There was a significant correlation (P<0.02) between nifedipine oxidation and paraoxon formation from parathion (200 µM) by human liver microsomes and with cytochrome P450 (CYP) 3A4/5 expression (P<0.05), although not with midazolam 1′-hydroxylation or testosterone 6β-hydroxylation. Paclitaxel 6′-hydroxylation and CYP2C8 expression correlated with paraoxon formation (P<0.01), indicating CYP2C8 involvement. Of nine recombinant P450 isoforms, CYPs 3A4, 3A5, 1A2 and 2D6 activated parathion to paraoxon at the highest rates (6.5, 8.5, 5.7 and 6.2 pmol/pmol P450 per h) with K m values of 12.6, 2.7, 1.5 and 9.2 µM, respectively. Similar K m values were seen with the human liver microsomes. These data indicate that CYP3A4/5 and CYP2C8, which constitute up to 40% of human liver P450s, are the most significant participants in the metabolism of parathion. However, several other isoforms could play an important role when CYP3A and CYP2C8 are poorly expressed due to environmental factors or the presence of a genetic polymorphism.
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References
Butler AM, Murray M (1997) Biotransformation of parathion in human liver: participation of CYP3A4 and its inactivation during microsomal parathion oxidation. J Pharmacol Exp Ther 280:966–973
Edwards RJ, Adams DA, Watts PS, Davies DS, Boobis AR (1998) Development of a comprehensive panel of antibodies against the major xenobiotic metabolising forms of cytochrome P450 in humans. Biochem Pharmacol 56:377–387
Gallo MA, Lawryk NJ (1991) Organic phosphorus pesticides. In: Hayes WJ, Laws ER (eds), Handbook of pesticide toxicology, vol 2. Academic Press, San Diego, pp 917–1123
Guengerich FP (1977) Separation and purification of multiple forms of microsomal cytochrome P450. J Biol Chem 252:3970–3979
Guengerich FP (1995) Human P450 enzymes. In: Oritiz de Montellano PR (ed) Cytochrome P450. Plenum Press, New York, pp 473–535
Kappers WA, Edwards RJ, Murray S, Boobis AR (2001) Diazinon is activated by CYP2C19 in human liver. Toxicol Appl Pharmacol 177:68–76
Kenworthy KE, Bloomer JC, Clarke SE, Houston JB (1999) CYP3A4 drug interactions: correlation of 10 in vitro probe substrates. B J Clin Pharmacol 48:716–727
King BP, Leathart JBS, Mutch E, Williams FM, Daly AK (2003) CYP3A5 phenotype-genotype correlations in a British population. B J Clin Pharmacol (in press)
Laemmli UK (1970) Cleavage of structural proteins during the assembly of the head of bacteriophage T7. Nature 227:680–685
Mutch E, Blain PG, Williams FM (1999) The role of metabolism in determining susceptibility to parathion toxicity in man. Toxicol Lett 107:177–187
Nelson DR, Koymans L, Kamataki T, Stegeman JJ et al. (1996) The P450 superfamily: update on new sequences, gene mapping, accession numbers and nomenclature. Pharmacogenetics 6:1–42
Norman BJ, Poore RE, Neal RA (1974) Studies of the binding of sulfur released in the mixed function oxidase-catalysed metabolism of diethyl p-nitrophenyl phosphorothionate (parathion) to diethyl p-nitrophenyl phosphate (paraoxon). Biochem Pharmacol 23:1733–1744
Perloff MD, von Moltke LL, Court MH, Kotegawa T et al. (2000) Midazolam and triazolam biotransformation in mouse and human liver microsomes: relative contribution of CYP3A and CYP2C isoforms. J Pharmacol Exp Ther 292:618–627
Sams C, Mason HJ, Rawbone R (2000) Evidence for the activation of organophosphate pesticides by cytochromes P450 3A4 and 2D6 in human liver. Toxicol Lett 116:217–221
Smith PK, Krohn RI, Hermanson GT et al. (1985) Measurement of protein using bicinchonic acid. Anal Biochem 150:76–85
Sonnichsen DS, Liu Q, Scheutz EG, Scheutz JD et al. (1995) Variability in human cytochrome P450 paclitaxel metabolism. J Pharmacol Exp Ther 275:566–575
Wang RW, Newton DJ, Scheri TD, Lu AYH (1997) Human cytochrome P450 3A4-catalysed testosterone 6β-hydroxylation and erythromycin N-demethylation. Drug Metab Disp 25:502–507
Williams JA, Ring BJ, Cantrell VE, Jones DR et al. (2002) Comparative metabolic capabilities of CYP3A4, CYP3A5 and CYP3A7. Drug Metab Disp 30:883–891
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This research was partly funded by the Colt Foundation.
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Mutch, E., Daly, A.K., Leathart, J.B.S. et al. Do multiple cytochrome P450 isoforms contribute to parathion metabolism in man?. Arch Toxicol 77, 313–320 (2003). https://doi.org/10.1007/s00204-003-0452-0
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DOI: https://doi.org/10.1007/s00204-003-0452-0