In Vitro Age-Dependent Enzymatic Metabolism of Chlorpyrifos and Chlorpyrifos-Oxon in Human Hepatic Microsomes and Chlorpyrifos-Oxon in Plasma

作者：Smith Jordan Ned^*; Timchalk Charles; Bartels Michael J; Poet Torka S

来源：Drug Metabolism and Disposition, 2011, 39(8): 1353-1362.

DOI：10.1124/dmd.111.038745

Age-dependent chlorpyrifos (CPF) metabolism was quantified by in vitro product formation in human hepatic microsomes (ages 13 days to 75 years) and plasma (ages 3 days to 43 years) with gas chromatography-mass spectrometry. Hepatic CPF cytochrome P450 desulfuration [CPF to chlorpyrifos-oxon (CPF-oxon)] and dearylation (CPF to 3,5,6-trichloro-2-pyridinol) V(max) values were 0.35 +/- 0.21 and 0.73 +/- 0.38 nmol . min(-1) . mg microsomal protein (-1) (mean +/- S. D.), respectively. The mean (+/- S.D.) hepatic CPF-oxon hydrolysis (chlorpyrifos-oxonase [CPFOase]) V(max) was 78 +/- 44 nmol . min(-1) . mg microsomal protein (-1). None of these hepatic measures demonstrated age-dependent relationships on a per microsomal protein basis using linear regression models. Ratios of CPF bioactivation to detoxification (CPF desulfuration to dearylation) V(max) values were consistent across ages. CPFOase in plasma demonstrated age-dependent increases on a volume of plasma basis, as did total plasma protein levels. Mean (+/- S.D.) CPF-oxon hydrolysis V(max) values for children <6 months of age and adults (>= 16 years) were 1900 +/- 660 and 6800 +/- 1600 nmol . min(-1) . ml(-1), respectively, and at environmental exposure levels, this high-capacity enzyme is likely to be sufficient even in infants. Plasma samples were phenotyped for paraoxonase status, and frequencies were 0.5, 0.4, and 0.1 for QQ, QR, and RR phenotypes, respectively. These results will be integrated into a physiologically based pharmacokinetic and pharmacodynamic model for CPF and, once integrated, will be useful for assessing biological response to CPF exposures across life stages.

• 出版日期2011-8