Metabolism cyclodienes

DDT Metabolism.-- The metabolism of DDT has been studied in R and S fish, following similar protocols to chlorinated cyclodiene metabolism organic extraction (acetonitrile), thin layer chromatography of organic extracts, and liquid scintillation counting of the resultant spots (4). When S and R fish were exposed to 60 yg/l of 14C-labelled , -DDT for 4 hr, radioactivity was found in the spots which co-chromatographed with... 

The formation of polar metabolites from nonpolar materials may actually facilitate monitoring programs—in many cases the polar chemicals are highly concentrated in certain body fluids such as bile and urine. On the other hand, materials such as certain cyclodienes and polychlorinated biphenyls, which are very lipid soluble and resistant to metabolism, may accumulate and these chemicals may persist in the environment and may be transferred via the food chain to man. There is also interest in these biotransformation processes in lower organisms since the simplicity of these systems may lead to a better understanding of the phylogenetic development of xenobiotic metabolism. 

Khan, M.A.Q., Feroz, M., and Sudershan, P. Metabolism of cyclodiene insecticides by fish, in Pesticide and Xenobiotic Metabolism in Aquatic Organisms, ACS Symposium Series 99 (Washington, DC American Chemical Society, 1979). 

Chlordane was introduced as an insecticide in 1945 and was the first cyclodiene insecticide that was used in agriculture (Eisler, 1990). It was the second most important organochlorine pesticide after toxaphene from 1976 to 1977 (Stansley Roscoe, 1999). It has been used on agricultural crops and extensively in the control of termites (Smith, 1991). Chlordane and heptachlor can be metabolized into two persistent (oxygenated) epoxides—oxychlordane and heptachlor epoxide—in mammals (Nomeir Hajjar, 1987) such that the two compounds are always measured together with chlordane and heptachlor. 

Several investigations (38-40) between i960 and 1965 finally dispelled the myth of dieldrin s metabolic inertness in mammals and since then numerous laboratories have shown that cyclodienes conform to the established principles of drug metabolism (4l). Molecular structure has a profound influence on the exposure of the non-chlorinated portions of these molecules to enzymatic attack and the low persistence of endrin, as compared to dieldrin, in mammalian tissues appears largely due to the stereochemical difference (42). The biotransformations of dieldrin are summarised in Figure 5 ... 

Epoxide rings of alkene and arene compounds are hydrated to form trans-diols. The enzymes that catalyze the addition of a molecule of water to an epoxide ring to yield diols are called epoxide hydrolases (also known as epoxide hydrases). Epoxide hydrolase activity has been detected in numerous species of insects. Enzymatic epoxide hydration of certain cyclodiene insecticides and their analogs has been demonstrated in the housefly, blowfly (Calliphora erythrocephala), yellow mealworm (Tenebrio molitor), Madagascar cockroach (Gromphadorhina portentosa), southern army worm (Spodoptera eridania), and red flour beetle (Tribolium castaneum). Epoxide hydrolase is also important in the metabolism of juvenile... 

As with other organochlorine cyclodiene compounds, chlordane is metabolized mainly by the liver microsomal cytochrome P-450 system. Several metabolites are produced including chlordene chlor-ohydrin, monohydroxylated dihydrochlordene, oxy-chlordane, and relatively smaller but similar amounts of 1,2-dichlorochlordene, l-hydroxy-2-chloro-chlordene, l-hydroxy-2-chloro-2,3-epoxychlordene,... 

Researchers were also able to establish the link between declines of other predatory species such as the European sparrowhawk and the use of organo-chlorine pesticides other than DDT. For instance, the cyclodiene insecticides aldrin, dieldrin, and he-ptachlor used as seed treatments caused massive mortality of both seed-eating species and their predators. All of the insecticides had the following points in common they were highly soluble in fats and refractory to metabolism. The impacts on the predatory species typically take place in periods of food stress when fat soluble residues are released from fat stores and returned into general circulation. In a food-stressed individual, the brain remains as the most lipid rich tissue and this is where contaminants move to. Toxicity results when threshold values in brain tissue are exceeded. At sublethal levels, documented effects of cyclodiene insecticides in birds have included changes in their reproductive, social, and avoidance behaviors. 

Finally, conventional pesticides under certain conditions may induce growth abnormalities which preclude survival of the insects concerned. This can be manifest during pupation and eclosion of adults. It appears to result from sublethal exposure to certain pesticides such as the cyclodienes, where the products of metabolism are toxic and must be excreted to complete the detoxification process. If excretion of the metabolites has not occurred before the pre-pupal stage is reached, they remain in the insect and interfere with morphogenesis. 

The cyclodienes, particularly aldrin, dieldrin, and endrin, are considered unsafe for any kind of use. Lindane, on the other hand, has high selectivity in favour of Man. It is included in the World s principal pharmacopoeias as an insecticide, acaricide, and larvicide. A 0.2% alcoholic solution is applied topically for head lice and a 1 % emulsion is employed in the treatment of scabies, in humans. The use of DDT in human medicine, for similar purposes, has greatly diminished in the last decade. It must, however, be pointed out that it has a high safety record in Man, and that government bans on its use are concerned with its accumulation in the food chains of birds and fish where it interferes with the calcium metabolism of shells and bones, respectively (see p. 96). In 1956, Hayes, Durham and Cueto, of the USA Public Health Service, fed 35 mg of DDT per man per day (i.e. 200 times the highest average dietary intake of that time in the USA) to human volunteers for 18 months. None of the subjects developed any symptom related to this chemical. 

Pyroles and phenylpyrozoles. The pyroles such as chlorfenapyr act as metabolic toxins and work by uncoupling oxidative phosphorylation in the mitochondria. In contrast the phenylpyrozole, fipronil has a mode of action similar to the cyclodiens (e.g. aldrin) and acts as an axonic poison. 

---