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The Relationship between PON1 Phenotype and PON1-192 Genotype in Detoxification of Three Oxons by Human Liver

Lookup NU author(s): Dr Elaine Mutch, Professor Ann Daly, Professor Faith Williams

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Abstract

PON1 is an esterase which is synthesised in the liver and secreted into the blood serum. It hydrolyses the active metabolites (oxons) of organophosphate pesticides (OPs) such as parathion, chlorpyrifos and diazinon. Human PON1 has a polymorphism in the coding region (Q192R) which results in two isoforms, Q (Glu) and R (Arg), which differ in their hydrolytic activity towards OP oxons. This study aimed i) to define the rates of paraoxon, chlorpyrifos-oxon and diazoxon hydrolysis by a panel of human liver microsomes (n=27 or n=19, diazoxon hydrolysis) ii) to determine the relationship between hydrolysis of the oxons and PON1192 genotype. Genomic DNA was extracted from the livers using phenol/chloroform and single strand conformational polymorphism (SSCP) analysis of the PCR product was used to separate the three genotypes. As with serum, individuals with the RR genotype preferentially hydrolysed paraoxon in liver, while chlorpyrifos-oxon and diazoxon were hydrolysed within the three genotypes at similar rates. This study showed wide rates of hydrolysis of the three oxons between individuals with the same PON1192 genotype, indicating that functional activity may be of more importance than genotype alone. Following an occupational dermal exposure to the parent OP, the OP would be activated by the P450s during first-pass metabolism in the liver. The small amount of oxon formed would be rapidly hydrolysed by hepatic PON1 (and other esterases) and therefore the individual’s functional expression of PON1 and P450 may be a more relevant determinant of susceptibility to OP toxicity than PON1 genotype alone. Table 1 Oxon hydrolysis by human liver microsomes expressed as nmol/min/mg protein. PON1 Q192R Genotype Paraoxon (1mM) hydrolysis Chlorpyrifos-oxon (500µM) hydrolysis Diazoxon (500µM) hydrolysis All 0.170-9.60 (1.43) 17.9-288.1 (95.9) 42.7-243.6 (76.1) QQ 0.173-4.42 (1.04) 17.9-240.1 (95.9) 42.7-176.1 (88.2) QR 0.680-9.60 (1.20) 34.4-288.1 (44.4) 47.4-185.6 (114.3) RR 2.53-5.96 (3.82) 39.0-221.7 (134.8) 49.5-243.6 (58.1)


Publication metadata

Author(s): Mutch E, Daly AK, Williams FM

Publication type: Article

Publication status: Published

Journal: Drug Metabolism and Disposition

Year: 2007

Volume: 35

Issue: 2

Pages: 315-320

ISSN (print): 0090-9556

ISSN (electronic): 1521-009X

Publisher: American Society for Pharmacology and Experimental Therapeutics

URL: http://dx.doi.org/10.1124/dmd.106.013193

DOI: 10.1124/dmd.106.013193

Notes: Part of this research was given as invited oral presentations at both international PON1 conferences; in Ann Arbor, USA (2004)and Debrecen, Hungary (2006).


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