Parathion mammalian microsomes

One of the most extensively studied phosphorothionate esters from the standpoint of mammalian metabolism is the insecticide parathion. The majority of this paper will center on what is known of the mechanism of mammalian microsomal metabolism of this compound. 

The reactivity of the individual O—P insecticides is determined by the magnitude of the electrophilic character of the phosphoms atom, the strength of the bond P—X, and the steric effects of the substituents. The electrophilic nature of the central P atom is determined by the relative positions of the shared electron pairs, between atoms bonded to phosphoms, and is a function of the relative electronegativities of the two atoms in each bond (P, 2.1 O, 3.5 S, 2.5 N, 3.0 and C, 2.5). Therefore, it is clear that in phosphate esters (P=0) the phosphoms is much more electrophilic and these are more reactive than phosphorothioate esters (P=S). The latter generally are so stable as to be relatively unreactive with AChE. They owe their biological activity to m vivo oxidation by a microsomal oxidase, a reaction that takes place in insect gut and fat body tissues and in the mammalian Hver. A typical example is the oxidation of parathion (61) to paraoxon [311-45-5] (110). 

The studies described above have been carried out using hepatic microsomes from various mammalian species and purified cytochrome P-450-containing monooxygenases obtained from the livers of rabbits and rats. Additional studies have indicated the microsomes from rabbit ( ) and rat lung brain 21) also metabolize parathion in a manner similar to mammalian liver. 

Extraordinary selectivity has been accomplished with the parathion-type of insecticide by incorporating Q or CH3 groups in the meta position of the aryl ring. These groups interact sterically with acetylcholinesterase (AChE), increasing the affinity for the insect enzyme and decreasing it with the mammalian enzyme. Selectivity also is enhanced by differences in the rates of microsomal oxidation of P=S to P=0 and in hydrolytic detoxication between insects and mammals. The compounds, fenitrothion, fenthion, ronnel, bromophos, iodofenfos, chlorpyrifos—methyl, and pirimiphos —methyl, and dicapthon are used widely in public health, household, and agricultural pest control. 

Reductive reactions, like oxidation, are carried out at different rates by enzyme preparations from different species. Microsomes from mammalian liver are 18 times or more higher in azoreductase activity and more than 20 times higher in nitroreductase activity than those from fish liver. Although relatively inactive in nitroreductase, fish can reduce the nitro group of parathion, suggesting multiple forms of reductase enzymes. 

Figure 9.2 Initial rates of parathion desulfuration by hepatic microsomes of representative males and females of different mammalian species. Activity was determined at 37°C using an initial substrate concentration of 2 x 10 1 M parathion. The bars represent the mean activities (nmol of paraoxon/min/mg protein) of the number of animals shown. The lines represent the standard deviations of the mean values. (From Whitehouse, L.W. and Ecobichon, D.J., Pestic. Biochem. Physiol., 5, 314,1975. With permission.)...

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