Hydroxylation and cyclization reactions involved in the metabolism of tri-O-cresyl phosphate

doi:10.1016/0006-2952(62)90056-4

Biochemical Pharmacology

Volume 11, Issues 4–5, April–May 1962, Pages 337-352

https://doi.org/10.1016/0006-2952(62)90056-4 Get rights and content

Abstract

Tri-o-cresyl phosphate is metabolized in rats by hydroxylation and cyclization of the hydroxymethyl derivatives. Indirect evidence was obtained for two intermediates, di-(o-cresyl) mono-o-hydroxymethylphenyl phosphate and di-(o-hydroxymethyl-phenyl)mono-o-cresyl phosphate. These intermediates cyclize spontaneously. The principal cyclic phosphate formed was 2-(o-cresyl)-4H-1:3:2-benzodioxaphosphoran-2-one, as ascertained by isolation and synthesis. Evidence is also presented for 2-(o-hydroxymethylphenyl)-4H-1:3:2-benzodioxaphosphoran-2-one and 2-(o-hydroxy-benzyl)-4H-1:3:2-benzodioxaphosphoran-2-one, as either metabolites or products formed on spontaneous cyclization. The primary cyclic metabolite (see above) hydrolyses in mild alkali or reacts with chymotrypsin by cleavage of the cyclic phosphate at the P—O-aryl bond. The deleterious biological activity of tri-o-cresyl phosphate appears to result from esterase inhibition by these cyclic phosphate metabolites.

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Tri-ortho-cresyl phosphate (TOCP), an organophosphorus compound (OP), which is widely used as plasticizer, flame retardant and other industrial products, has been reported to cause multiple toxicities including neurotoxicity and reproductive toxicity. However, it remains to be elusive whether TOCP induces hepatotoxicity. The purpose of this study was to investigate the effect of TOCP on hepatocytes and the lipid metabolism in particular. The adult mice were given a single dose of TOCP (800 mg/kg, p.o.) and the histological changes in liver tissue and lipid content in serum were determined. The results showed that more vacuoles and lipid droplets were observed in the liver of the mice exposed to TOCP. And triglyceride concentrations in serum and liver tissue significantly increased. However, the histopathological changes of the liver and the elevated triglyceride levels in the exposed mice can be reversed by endoplasmic reticulum (ER) stress inhibitor 4-phenylbutyric acid and mTOR signal inhibitor rapamycin. It was also found that the changes of expression levels of the biomarkers of ER stress and mTOR signaling pathway, such as GRP78, CHOP, and p-mTOR, in the exposed mice were consistent with those observed in the cultured primary hepatocytes treated with the same chemicals. These results showed that TOCP activated mTOR signal and ER stress to induce de novo lipid synthesis, which led to the hepatic steatosis in mouse.
Occurrence and in vitro toxicity of organic compounds in urban background PM<inf>2.5</inf>
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The toxicity of TOCP is described as dependent on its metabolic activation by the cytochrome P450 system (Eto et al., 1962), and might therefore be underestimated in this study. The activation leads to the formation of cyclic saligenin phosphate esters, which induce the toxic effect of TOCP (Eto et al., 1962; Lorke et al., 2016). This metabolic activation is also described for phosphorothioates and takes place in the brain, having a major role in acute toxicity (Sanchez-Hernandez and Walker, 2000).
This study describes the chemical composition and in vitro toxicity of the organic fraction of fine particulate matter (PM_2.5) at an urban background site, which receives emissions either from Frankfurt international airport or the city centre, respectively. We analysed the chemical composition of filter extracts (PM_2.5) using ultrahigh-performance liquid chromatography coupled to a high-resolution mass spectrometer, followed by a non-target analysis. In parallel, we applied the bulk of the filter extracts to a Microtox and acetylcholinesterase-inhibition assay for in vitro toxicity testing. We find that both the chemical composition and toxicity depend on the prevailing wind directions, and the airport operating condition, respectively. The occurrence of the airport marker compounds tricresyl phosphate and pentaerythritol esters depends on the time of the day, reflecting the night flight ban as well as an airport strike event during November 2019. We compared the organic aerosol composition and toxicity from the airport wind-sector against the city centre wind-sector. We find that urban background aerosol shows a higher baseline toxicity and acetylcholinesterase inhibition compared to rural PM_2.5 that is advected over the airport. Our results indicate that the concentration and individual composition of PM_2.5 influence the toxicity. Suspected drivers of the acetylcholinesterase inhibition are i.e. organophosphorus esters like triphenyl phosphate and cresyldiphenyl phosphate, and the non-ionic surfactant 4-tert-octylphenol ethoxylate. However, further research is necessary to unambiguously identify harmful organic air pollutants and their sources and quantify concentration levels at which adverse effects in humans and the environment can occur.
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The use of bioscavengers of organophosphorus (OPs) agents is the most effective alternative approach for the neutralization or detoxification of OPs for decontamination under soft conditions, pretreatment, and postexposure treatment of poisoning by nerve agents. Administered bioscavengers neutralize toxic molecules in the bloodstream before they reach their biological targets, thus providing protection against poisoning.
First-generation bioscavengers are stoichiometric scavengers. Among them, human butyrylcholinesterase has proved to be safe and effective for protection against poisoning by organophosphorus agents. However, stoichiometric neutralization of OPs needs the administration of huge amounts of costly biopharmaceuticals. Catalytic bioscavengers that neutralize OPs with a turnover are administered at much lower doses for the same efficacy. Thus, introduction of catalytic bioscavengers in medical countermeasures to OP poisoning will be a considerable improvement. The most effective catalytic bioscavengers are enzymes. Catalytic bioscavengers could also be used as active components in topical skin protectants and for decontamination of skin, mucosa, and wounds under mild conditions.
The most promising enzymes are engineered mutants of mammalian paraoxonase and bacterial phosphotriesterases. However, research into other enzymes, prolidases, oxidases, engineered cholinesterases (ChEs) and carboxylesterases, and catalytic antibodies is actively pursued. Certain secondary biological targets of OPs are also potential catalytic bioscavengers, in particular serum albumin that reacts with OPs and self-reactivates.
Because OPs are hemisubstrates of ChEs, a detailed description of mechanisms of phosphylated ChE self-reactivation is presented in the perspective of designing ChE mutants hydrolyzing OPs at a high rate.
The implementation of strategies and methods of protein engineering allows large-scale production of enzymes, displaying improved catalytic properties and not susceptible to inducing iatrogenic effects. Research on immunologically compatible enzyme formulations stable in the bloodstream and during storage is another field of investigation. This, in particular, includes nanoencapsulation of bioscavengers. Lastly, gene therapy and clustered regularly interspaced short palindromic repeat technology are promising, but still in infancy for safe use.
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This structurally, mechanistically, and functionally diverse family of enzymes is found in nearly all human tissues where they hydrolyze physiologically essential esters, drugs, and toxins. Several esterases are found in human blood: butyrylcholinesterase and paraoxonase in plasma and acetylcholinesterase, esterase D (ESD), and neuropathy target esterase in blood cells. In contrast to rodents, human plasma contains no carboxylesterase. Human red blood cells contain glycolipid-anchored acetylcholinesterase outside and ESD inside the cells. Liver, lung, intestine, and other tissues contain a total of 31 esterases including 4 carboxylesterases, 2 paraoxonases, 14 thioesterases, 6 lipases, 2 cholinesterases, 1 methylesterase, 1 platelet-activating factor acetylhydrolase, and 1 sialate O-acetylesterase. Esterases detoxicate cocaine, organophosphorus pesticides, pyrethroid insecticides, nerve agents, succinylcholine, mivacurium, ritalin, aspirin, esmolol, and demerol. The prodrugs irinotecan, bambuterol, Tamiflu, trandolapril, imidapril, temocapril, and ciclesonide are converted into active drugs by esterases. Genetic variants of human butyrylcholinesterase, carboxylesterase, paraoxonase, and ESD affect the metabolism of ester drugs. A His322 to Asn mutation in human acetylcholinesterase has no effect on catalytic activity but does define an YT2 blood group antibody epitope. Catalytic triad (Ser-His-Glu/Asp) of butyrylcholinesterase, acetylcholinesterase, carboxylesterase, and ESD is covalently inhibited by organophosphates rendering nerve agents and organophosphorus pesticides acutely toxic primarily due to inhibition of acetylcholinesterase. The serine esterases have similar tertiary, alpha/beta hydrolase fold protein structures different from six-bladed beta-propeller structure of paraoxonase.
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Citation Excerpt :
For each test, P-values less than 0.05 (P < 0.05) were considered statistically significant. SCOTP was synthesized in our laboratory according to Eto et al. [17] and Nomeir and Abou-Donia [19]. The synthesized SCOTP was identified by 1H NMR and ESI-MS. 1H NMR (400 MHz, CDCl3): δ = 7.26–7.35 (m, 2H), 7.06–7.18 (m, 6H), 5.49 (d, 2H), 2.20 (s, 3H) ppm; ESI-MS: (m/z,%) = 277 [M+H]+.
Tri-ortho-cresyl phosphate (TOCP) has been widely used as plasticizers, plastic softeners, and flame-retardants in industry, which can be metabolized to High-toxic saligenin cyclic-o-tolyl phosphate (SCOTP). Our previous results found that TOCP could disrupt the seminiferous epithelium in the testis and induce autophagy of rat spermatogonial stem cells. Little is known about the toxic effect of SCOTP on rat spermatogonial stem cells. The present study showed that SCOTP decreased viability of rat spermatogonial stem cells in a dose-dependent manner. Both LC3-II and the ratio of LC3-II/LC3-I were significantly increased; autophagy proteins atg5 and Beclin 1 were also markedly increased after treatment with SCOTP, indicating SCOTP could induce autophagy of the cells. Ultrastructural observation under the transmission electron microscopy (TEM) indicated that there were autophagic vacuoles in the cytoplasm in the SCOTP-treated cells. However, cell cycle arrest was not observed by flow cytometry; and the mRNA levels of p21, p27, p53 and cyclin D1 in the cells were also not affected by SCOTP. Meanwhile, SCOTP didn't induce apoptosis of the cells. In summary, we showed that SCOTP could induce autophagy of rat spermatogonial stem cells, without affecting cell cycle and apoptosis.
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Many potentially suitable AFRs are already in use, despite the absence of a full profile of their environmental behavior and toxicological properties. To prioritize the suitability of some selected halogenated and non-halogenated organophosphorous flame retardants and inorganic halogen-free flame retardants, the available neurotoxic data of these AFRs are discussed. The suitability of the AFRs is rank-ordered and combined with human exposure data (serum concentrations, breast milk concentrations and house dust concentrations) and physicochemical properties (useful to predict e.g. bioavailability and persistence in the environment) for a first semi-quantitative risk assessment of the AFRs.
As can be concluded from the reviewed data, several BFRs and AFRs share some neurotoxic effects and modes of action. Moreover, the available neurotoxicity data indicate that some AFRs may be suitable substitutes for BFRs. However, proper risk assessment is hampered by an overall scarcity of data, particularly regarding environmental persistence, human exposure levels, and the formation of breakdown products and possible metabolites as well as their toxicity. Until these data gaps in environmental behavioral and toxicological profiles are filled, large scale use of these chemicals should be cautioned.

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^∗: Project associate. Permanent address: Department of Agricultural Chemistry, Kyushu University, Fukuoka, Japan.

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Hydroxylation and cyclization reactions involved in the metabolism of tri-O-cresyl phosphate

Abstract

Biochem. Pharmacol.

Biochem. Pharmacol.

Arch. Exp. Path. Pharmak.

J. Amer. Chem. Soc.

Brit.J. Indust. Med.

Publ. Hlth Rep., Wash.

Nat. Inst. Hlth. Bull.

World Neurol.

Advanc. Pest Control Res.

Biochem. J.

Nature, London.

Nature, Lond.

A Manual of Paper Chromatography and Paper Electrophoresis

A Manual of Paper Chromatography and Paper Electrophoresis

J. Agric. Food Chem.