Paraoxonase 1 (PON1) modulates the toxicity of mixed organophosphorus compounds

Abstract

A transgenic mouse model of the human hPON1 Q192R polymorphism was used to address the role of paraoxonase (PON1) in modulating toxicity associated with exposure to mixtures of organophosphorus (OP) compounds. Chlorpyrifos oxon (CPO), diazoxon (DZO), and paraoxon (PO) are potent inhibitors of carboxylesterases (CaE). We hypothesized that a prior exposure to these OPs would increase sensitivity to malaoxon (MO), a CaE substrate, and the degree of the effect would vary among PON1 genotypes if the OP was a physiologically significant PON1 substrate in vivo. CPO and DZO are detoxified by PON1. For CPO hydrolysis, hPON1 R192 has a higher catalytic efficiency than hPON1 Q192 . For DZO hydrolysis, the two alloforms have nearly equal catalytic efficiencies. For PO hydrolysis, the catalytic efficiency of PON1 is too low to be physiologically relevant. When wild-type mice were exposed dermally to CPO, DZO, or PO followed 4-h later by increasing doses of MO, toxicity was increased compared to mice receiving MO alone, presumably due to CaE inhibition. Potentiation of MO toxicity by CPO and DZO was greater in PON1 −/− mice, which have greatly reduced capacity to detoxify CPO or DZO. Potentiation by CPO was more pronounced in hPON1 Q192 mice than in hPON1 R192 mice due to the decreased efficiency of hPON1 Q192 for detoxifying CPO. Potentiation by DZO was similar in hPON1 Q192 and hPON1 R192 mice, which are equally efficient at hydrolyzing DZO. Potentiation by PO was equivalent among all four genotypes. These results indicate that PON1 status can have a major influence on CaE-mediated detoxication of OP compounds.

Joint toxicity of fluoroquinolone and tetracycline antibiotics to zebrafish (<i>Danio rerio</i>) based on biochemical biomarkers and histopathological observation

“…The MDA (nmol/mg prot) content from zebrafish liver was determined by thiobarbituric acid (TBA) colorimetry (Li et al, 2009). AChE activity (U/mg prot) from zebrafish brain was analyzed using a commercial AChE detection kit (Guangdong Dongsheng, Guangzhou, China) according to manufacturer's instructions and a previous publication (Jansen et al, 2009). Enzymatic activities were determined in triplicate and expressed as nanomoles of substrate hydrolyzed per minute per mg of protein.…”

Paraoxonase 1: Structure, Function, and Polymorphisms

“…With paraoxon, potentiation of malaoxon toxicity was similar in all mouse genotypes. These results show that low doses of major OP insecticides can potentiate the toxicity of malaoxon, and that PON1 status can significantly influence the outcome of the interaction between the OPs and malaoxon, in a PON1 substrate-dependent manner (Jansen et al, 2009).…”

“…It has been long known that inhibition of CarE leads to potentiation of maloxon toxicity (Cohen and Murphy, 1971). Chlorpyrifos oxon, diazoxon, and paraoxon were found to be potent inhibitors of plasma and liver CarE in vitro (Jansen et al, 2009). When given in vivo at doses that caused only minimal inhibition of brain AChE, all three compounds significantly inhibited plasma CarE activity.…”

“…A recent study (Jansen et al, 2009) showed that three OPs (chlorpyrifos oxon, diazoxon, and paraoxon) can potentiate the toxicity of malaoxon, and that the degree of potentiation is dependent on PON1 status. As said earlier, chlorpyrifos oxon is metabolized by PON1 in vivo, particularly by the R192 allozyme; diazoxon is also metabolized by PON1 in vivo, though equally by the two PON1 192 allozymes, while paraoxon is not appreciably metabolized by PON1 in vivo.…”

Zebrafish locomotor capacity and brain acetylcholinesterase activity is altered by Aphanizomenon flos-aquae DC-1 aphantoxins

“…Brain AChE activity was determined using a commercial AChE detection kit (Guangdong Dongsheng, China) according to the manufacturer's instructions and the previous methods (Jansen et al, 2009). Briefly, ∼45 mg frozen whole brains (−40 • C) were homogenized (homogenizer; IKA ® , Werke, Germany) in 405 L (w:v 1:9) 0.86% w/v ice-cold physiological saline (4 • C ice bath, pH 7.2) for 30 s. Supernatants were centrifuged to harvest enzymatic stock extracts (5900 × g, 4 • C, 10 min).…”