Present knowledge concerning biochemical conjugations stemmed from the isolation and identification of conjugates from normal and pathological animal urine during the last century. As early as 1842, the formation of hippuric acid was conclusively established by Keller following self-administration of benzoic acid. During the latter part of the last century, conjugations such as the synthesis of sulfates, glucuronides, and ornithine conjugates were discovered, and reactions involving mercapturic acid formation, methylation, acetylation, and cyanide detoxication were recognized. Glutamine conjugation was demonstrated in man in 1914 and glucoside conjugation in plants and insects in 1938 and 1953, respectively (Smith and Williams, 1970; Williams, 1959, 1967). During the past two decades, considerable attention has centred around the biochemical conjugations of certain naturally occurring body constituents such as sterols, bile acids, steroid hormones, glycoproteins, and mucopolysaccharides. Consequently, a number of new conjugations have been discovered (Layne, 1970).

Enzymatic Conjugation and Insecticide Metabolism

Biological Activity of Pesticide Conjugates

Glucuronidation mechanisms in the rat and their significance in the metabolism of insecticides

Metabolism of insecticides by conjugation mechanisms.

The blood kinetics of carbaryl were followed over 24 h after oral administration of 14C-carbaryl at 20 mg kg (0.17 mu Ci mg-1) in control animals and in animals with an altered liver function (70% hepatectomy or tranylcypromine treatment). The variations in the primary toxicity of carbaryl were assessed by measuring the inhibition of the plasma and erythrocyte cholinesterases and by evaluation of the lethal doses. The 14C radioactivity in the blood and, in parallel, cholinesterase inhibition were maintained at a higher level in animals with an altered hepatic function. A study of acute toxicity also showed a decrease of the LD50 (91 mg kg-1 with tranylcypromine, 342 mg kg-1 in the hepatectomized group) in the treated animals, with respect to the controls (585 mg kg-1). In all cases, tranylcypromine had a greater effect on blood kinetics, cholinesterase inhibition and LD50 than did 70% hepatectomy.

Influence of experimental hepatic impairment on the toxicokinetics and the anticholinesterase activity of carbaryl in the rat.

Effect of monoamine oxidase inhibitors on carbaryl metabolism.

The rate of carbaryl metabolism by rats was decreased by simultaneously administering drugs commonly referred to as monoamine oxidase inhibitors and by prolonged exposure of the animals to one of the drugs in the drinking water. Conjugative mechanisms of metabolism were affected most by the drugs although oxidative and hydroxylative metabolism rates were reduced to some degree. Decreasing the rate of metabolism resulted in a slower rate of excretion of the carbamate from rats treated with the drugs. Tranylcypromine at 50 mg/kg, e.g., reduced excretion of carbaryl-14C equivalents from rats by 50% during the 1st 48 hours after treatment. A rat intestine enzyme system, fortified with UDPGA, conjugated 1-naphthol but did not metabolize carbaryl. This in vitro conjugating system was inhibited by the monoamine oxidase inhibitors. The effect of these drugs on conjugation was not sufficient to suggest that they might enhance the action of pesticides under practical conditions. However, the data do demonstrate that conjugation enzyme systems are sensitive to certain foreign chemicals and that more effective inhibitors of conjugation could be important in the safety and efficacy of chemicals used to control insect pests.

T. Lin

Papers

Effect of monoamine oxidase inhibitors on carbaryl metabolism.

Modification of Carbaryl Metabolism in Rats with Monoamine Oxidase Inhibitors