Do multiple cytochrome P450 isoforms contribute to parathion metabolism in man?
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 micro M) by human liver microsomes and with cytochrome P450 (CYP) 3A4/5 expression ( P<0.05), although not with midazolam 1'-hydroxylation or testosterone 6beta-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 micro M, 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.
Mutch
Elaine
E
Department of Environmental Medicine, School of Clinical and Laboratory Sciences, The Medical School, University of Newcastle, NE2 4HH, Newcastle, UK, elaine.mutch@newcastle.ac.uk
Daly
Ann K
AK
Leathart
Julian B S
JB
Blain
Peter G
PG
Williams
Faith M
FM
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D065727:Cytochrome P-450 CYP2C8; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000493:pharmacokinetics; D004790:Enzyme Induction / Q000187:drug effects*; D006801:Humans; D007313:Insecta; D008617:Mephenytoin / Q000378:metabolism; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D008874:Midazolam / Q000378:metabolism; D009249:NADP; D009543:Nifedipine / Q000378:metabolism; D009596:Nitrophenols / Q000737:chemistry / Q000378:metabolism; D017239:Paclitaxel / Q000378:metabolism; D010261:Paraoxon / Q000737:chemistry / Q000378:metabolism; D010278:Parathion / Q000378:metabolism*; D013739:Testosterone / Q000378:metabolism
D009596:Nitrophenols; D013739:Testosterone; D009249:NADP; D010278:Parathion; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C450259:CYP2C8 protein, human; C104464:CYP3A protein, human; D065727:Cytochrome P-450 CYP2C8; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D009543:Nifedipine; D017239:Paclitaxel; D010261:Paraoxon; D008617:Mephenytoin; D008874:Midazolam; C024836:4-nitrophenol