Microsomal oxidase

Pyrethroids from Chiysanthemic Acid. The unsaturated side chains of the aHethrolone alcohol moieties of the natural pyrethrins are readily epoxidized by microsomal oxidases and converted to diols, thus detoxifying the insecticides. Esterification of chrysanthemic acid (9), R = CH3, with substituted ben2yl alcohols produces usehil insecticides barthrin [70-43-9J, 2-chloro-3,4-methylenedioxyben2yl (+)-i7j ,/n7 j -chrysanthemate, and dimethrin [70-38-2] 2,4-dimethylben2yl (+)-i7j ,/n7 j -chrysanthemate. These have alimited spectmm of insecticidal activity but are of very low mammalian toxicity, ie, rat oralLD s >20,000 mg/kg. 

Pyrethroids with Modified Chrysanthemate Esters. Newer pyrethroids incorporate optimized chrysanthemic acid components to retard detoxication by microsomal oxidases and these are esterified with a variety of optimized alcohol moieties therefore increasing persistence. 

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). 

Much work has demonstrated the presence of complex multienzyme monooxygenase systems within the endoplasmic reticulum of several mammalian species (for Reviews 1, 2, 3). These monooxygenase systems are responsible for the oxidative metabolism of many exogenous and endogenous substances, and the unusual non-specificity of these monooxygenase enzymes allows the metabolism of compounds with diverse chemical structures. Early work demonstrated that the terminal microsomal oxidase involved in xenobio-tic biotransformation was a hemoprotein, which has been subsequently named cytochrome P-450. 

Figure 3. Mutagenic activities of the promutagens cis- and Xrms-diallate and sulfallate, the proximate mutagen cis-diallate sulfoxide, and the ultimate mutagen 2-chloroacrolein, assayed with S. typhimurium strain TA 100 sensitive to base-pair substitution mutagens. The diallate isomers and sulfallate are not mutagenic without the S9 mix. S9 mix refers to a microsomal oxidase system prepared from rat liver and appropriate cofactors. The methodology is detailed in Refs. 6, 22, and 29.

Saeman, M.C. and J.E. Casida (1984). Metribuzin metabolites in mammals and liver microsomal oxidase systems Identification, synthesis, and reactions. J. Agric. Food Chem., 32 749-755. 

Figure 6. Biodegradable analogues of DDT (49-53). Arrows indicate points of attack by microsomal oxidases. Housefly toxicities relative to DDT (1.0) are underlined.

Increased activity of -eedyson-metabolizing enzymes and increase of microsomal oxidase activity. 

Yu, S.J. and Terriere, L.C., Metabolism of [,4C ]-hydroprene (ethyl 3,7,11-trimethyl-2,4-dodecadieno-ate) by microsomal oxidases and esterases from three species of Diptera, /. Agric. Food Chem.. 25,1076,1977. 

Gilbert, M.D. and Wilkinson, C.F., Microsomal oxidases in the honey bee, Apis mellifera L, Pestic. Biochem. Physiol., 4, 56,1974. 

Terriere, L.C. and Yu, S.J., Microsomal oxidases in the flesh fly (Sarcophagii bullata Parker) and the black blow fly [Phormia regina (Meigen)], Pestic. Biochent. Physiol., 6, 223,1976. 

Yu, S.J., Inheritance of insecticide resistance and microsomal oxidases in the diamondback moth (Lepidoptera Yponomeutidae), /. Econ. EntomoL, 86, 680,1993. 

In the course of cholestasis, lower concentrations of cytochrome P 450 are found together with increased activities of some microsomal oxidases. For this reason, the biotransformation of xenobiotics can be unpredictably and permanently altered. This is largely connected with the cholestasis-associated shift in bile acids from the periportal to the intermediary and perivenous zones. 

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