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Biological and Nonbiological Modifications of Organophosphorus Compounds*

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Biological and Nonbiological Modifications of Organophosphorus Compounds* Bull. Org. mond. Sante 1 Blull. Wld Hlth Org j1971, 44, 133-150 Biological and Nonbiological Modifications of Organophosphorus Compounds* W. C. DAUTERMAN 1 The general types of biological reaction that are most prominent in the modification of organophosphorus compounds involve the mixed-function oxidases, hydrolases, or transferases. In certain cases, more than one of these reactions may be involved at the same site on the pesticide molecule. Examples of various organophosphorus pesticides that are altered by oxidation, hydrolysis, alkyl- or aryl-group transfer, reduction, and conjugation are discussed. The increase or decrease in toxicity of a pesticide that can result from biological modification is emphasized. Non-biological transformations of organophosphorus compounds involve the effect ou the compounds of such factors as light, air, temperature, and solvent. These factors are discussed with special emphasis on desulfuration, rearrangement, and oxidation. Increasing emphasis is being given to research This information is important for an understanding on, and the development of, pesticides that will of the processes of intoxication, detoxification, and be effective for the control of insects but that will resistance. Information on the chemical behaviour minimize the " off-target " effects that arecharacteris- and reactions of organophosphorus compounds in tic of the chlorinated hydrocarbons. This trend a nonliving system, the environment, is essential involves both the more effective use ofcurrently avail- for the assessment of the potential hazards they able nonpersistent pesticides and the development present to human health, their longevity in the of new compounds. The organophosphorus com- environment, and their efficacy for the control of pounds are a chemical group of insecticides that insects. are characterized by their nonpersistence in the The metabolism of organophosphorus compounds environment as well as by their wide spectrum of by plants and animals, with special emphasis on activity. In order to utilize more effectively the isolated in vitro systems, is discussed in the first inhibitory power of the phosphate moiety in the section of this paper. The second section is devoted development of new compounds, a knowledge to environmental factors such as light, temperature, of the metabolism and fate of organophosphorus air, and solvent and their effects on nonbiological esters in various biological systems is necessary. modifications of organophosphorus compounds. BIOLOGICAL MODIFICATIONS The metabolism of organophosphorus insecticides Dauterman, 1970; Bull, 1970). This portion of the in plants and animals has been the subject of several review summarizes and compares the importance recent reviews (O'Brien, 1967; Hodgson, 1968; of the various biological processes by which plants Casida & Lykken, 1969; Lykken & Casida, 1969; and animals modify the chemical structure of Fukuto & Metcalf, 1969; Menzie, 1969; Menzer & insecticidally active organophosphorus compounds. Since the literature is so complex, by virtue of the * This study was supported in part by Grant ES-00044 large number of compounds, specific examples from the US Public Health Service. It is paper No. 3391 of have been chosen to illustrate the various types the Journal Series of the North Carolina State University Experiment Station, Raleigh, N.C., USA. of reaction. 1 Associate Professor, Department of Entomology, Organophosphorus insecticides are metabolized North Carolina State University, Raleigh, N.C., USA. by four general classes of reaction: (1) reactions 2622 - 133 - 134 W. C. DAUTERMAN Fig. 1 Oxidative desulfuration of parathion s 0 (C2H50)2 P Noz H (C2 H5 0)2 P 0 NO2 + So4 °K/ 02 parathion microsomes paraoxon Dahm (1970). involving the mixed-function oxidases, (2) reactions studies with microsomal preparations from cock- involving hydrolases, (3) transferase reactions, and roach fat body (Nakatsugawa & Dahm, 1965), (4) miscellaneous reactions. In certain cases, more rat liver (Neal, 1967a, 1967b; Nakatsugawa & than one of these reactions may be involved at a Dahm, 1967), and housefly abdomen (El Bashir & common site on the organophosphorus molecule. Oppenoorth, 1969) demonstrated that desulfuration Therefore the identification of the product is not of parathion was accomplished by a mixed-function necessarily indicative of either the type of biological oxidase system in the presence of NADPH and alteration or the route. molecular oxygen (Fig. 1). The sulfur atom is removed during the reaction in vitro and bound to the microsomes and the detached sulfur is found MIXED-FUNCTION OXIDASES in vivo as inorganic sulfate (Nakatsugawa & Dahm, The mixed-function oxidases are a group of 1967; Nakatsugawa et al., 1969b). It seems reason- enzymes that are important in the metabolism able to assume that the mixed-function oxidases of xenobiotics in mammals (Gillette et al., 1969) are responsible for the in vivo desulfuration of and insects (Hodgson & Plapp, 1970). The enzyme phosphorothioates in most other biological entities, systems are associated with the post-mitochrondrial although this reaction has not been demonstrated supernatant of plant or animal tissue homogenates in vitro in plants. and are derived from the endoplasmic reticulum. Oxidative N-dealkylation The particulate enzyme system has an essential requirement for NADPH and molecular oxygen The oxidative N-dealkylation by the mixed- in order to modify a xenobiotic. function oxidases of many nitrogen-containing xenobiotics in plants and animals is well documented Oxidative desulfuration (Frear et al., 1969; Gillette et al., 1969; Casida & Phosphorothioate and phosphorodithioate esters Lykken, 1969; Menzer & Dauterman, 1970). A are poor inhibitors of cholinesterases unless the typical example of this reaction is the N-demethyl- compounds are oxidatively desulfurated. This ation of dicrotophos and moncrotophos (Fig. 2). generally results in an increase in inhibition of the This reaction has been demonstrated to occur in target enzyme as well as in toxicity to the organism plants, mammals, and insects (Menzer & Casida, (Heath, 1961; O'Brien, 1960). The in vivo activation 1965; Bull & Lindquist, 1964, 1966; Lindquist & of parathion to paraoxon has been demonstrated Bull, 1967). Removal of the N-methyl groups pro- in both insects and mammals (Gage, 1953; Metcalf ceeds by the formation ofrelatively stable N-hydroxy- & March, 1953). Evidence for oxidative desulfu- methyl intermediates followed by the elimination ration has been demonstrated in both plants and of formaldehyde. The removal or modification of animals for a wide variety of insecticides: parathion- the N-substituents can result in an increase, a de- methyl (Hollingworth et al., 1967), malathion crease, or little change in toxicity. N-demethylation (O'Brien, 1957), dimethoate (Dauterman et al., 1960; has been reported to occur with schradan (Spencer Brady & Arthur, 1963), fenitrothion (Hollingworth et al., 1967), dimethoate (Sanderson & Edson, 1964; et al., 1967), and Supracide t (Bull, 1970). In vitro Lucier & Menzer, 1968, 1970), and famphur t (O'Brien et al., 1965). N-deethylation has been t Names against which this symbol appears are identified reported to occur with phosphamidon (Bull et al., in the Glossary on pages 445-446. 1967; Clemmons & Menzer, 1968). With phospha- BIOLOGICAL AND NONBIOLOGICAL MODIFICATIONS OF OP COMPOUNDS 135 Fig. 2 Oxidative N-dealkylation of dicrotophos * 0 0 ,. R =(CH30)2 Po c = CH C- CH3 N -h ydroxymethyl N-hydroxymethyl dicrotophos dicrotophos monocrotophos monocrotophos amide CH3 CH 3 CH3 'H2 OH / / / RH-N R R N RN H2 R-N R-N - CH3 CH20H H H L D50(mg/kg) 18 8 12 3 mouse P I 50 Fly ChE 7.2 7.0 6.8 6.9 6.5 * Menzer & Casida (1965). midon the N-ethyl groups are sequentially hydroxy- phosphatase enzyme. Only recently has in vitro evi- lated on the a-carbon and then eliminated as dence been presented to indicate that other mecha- acetaldehyde. In all cases studied the relative con- nisms are also responsible for the formation of centrations of the products formed were usually dealkylated metabolites (see also the sections on small but all the metabolites had anticholinesterase hydrolases and transferases, below). Donninger properties. et al. (1967) demonstrated that chlorfenvinphos was oxidatively O-deethylated by liver microsomes Oxidative 0-dealkylation in the presence of NADPH and oxygen (Fig. 3). Cleavage of organophosphorus triesters to diesters The reaction resulted in the isolation of deethyl results in relatively nontoxic metabolites. Since the chlorfenvinphos and acetaldehyde and it was postu- isolation and identification by Plapp & Casida (1958) lated that an unstable 1-hydroxyethyl intermediate of metabolites that were the result of alkyl-phosphate was formed, which subsequently broke down. Oxi- cleavage, this reaction has generally been regarded dative demethylation has also been demonstrated as being of a hydrolytic nature, catalysed by a to occur with Gardona,t the dimethyl analogue Fig. 3 Oxidative O-deethylation of chlorfenvinphos * OH 1~~~~~~~0 CH3CH O 0C HO 0 C0 O 0 C V \POC (C2H50)2 P C I'loP0COC CH+C3CF acl C2H5 0 "c H C Cl CH3CH2 HCCI H C C L _j postu l a ted intermediate * Donninger et al. (1 967). 136 W. C. DAUTERMAN Fig. 4 Oxidative dearylation of diazinon * I~~~~ s S NADPH 11 (C2H5 °)2 P 0 CH(CH3)2 P H 02 (C2H50)2 0 CH3 microsomes 0 NADPH ,, (C2H50)2 P 0 N> CH (CH3)2 o (C2H50)2 P 0H 02 House f y abdomen OH3 microsomes *Yang et al. (1971). of chlorfenvinphos (Hutson et al., 1968a).
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