Toxicity of metabolites of dieldrin, photodieldrin, and endrin in the cockroach

Kadous, A.A.; Matsumura, Fumio

doi:10.1007/bf01056373

Cited by 8 publications

(6 citation statements)

References 19 publications

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“…49 This compound is less toxic to insects, as compared to dieldrin. 50 The third group aimed to assess the combined effects of altering the polar moiety (epoxide to olefin) along with the 3dimensional structure. The two compounds in this group are based on aldrin, with isodrin being its isomer, and desmethylene aldrin lacking the methano bridge found in aldrin and dieldrin.…”

Section: ■ Discussionmentioning

confidence: 99%

Cellular Localization of Dieldrin and Structure–Activity Relationship of Dieldrin Analogues in Dopaminergic Cells

Allen

Florang

Davenport

et al. 2013

Chem. Res. Toxicol.

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The incidence of Parkinson’s disease (PD) correlates with environmental exposure to pesticides, such as the organochlorine insecticide, dieldrin. Previous studies found an increased concentration of the pesticide in the striatal region of the brains of PD patients and also that dieldrin adversely affects cellular processes associated with PD. These processes include mitochondrial function and reactive oxygen species production. However, the mechanism and specific cellular targets responsible for dieldrin-mediated cellular dysfunction and the structural components of dieldrin contributing to its toxicity (toxicophore) have not been fully defined. In order to identify the toxicophore of dieldrin, a structure–activity approach was used, with the toxicity profiles of numerous analogues of dieldrin (including aldrin, endrin, and cis-aldrin diol) assessed in PC6-3 cells. The MTT and lactate dehydrogenase (LDH) assays were used to monitor cell viability and membrane permeability after treatment with each compound. Cellular assays monitoring ROS production and extracellular dopamine metabolite levels were also used. Structure and stereochemistry for dieldrin were found to be very important for toxicity and other end points measured. Small changes in structure for dieldrin (e.g., comparison to the stereoisomer endrin) yielded significant differences in toxicity. Interestingly, the cis-diol metabolite of dieldrin was found to be significantly more toxic than the parent compound. Disruption of dopamine catabolism yielded elevated levels of the neurotoxin, 3,4-dihydroxyphenylacetaldehyde, for many organochlorines. Comparisons of the toxicity profiles for each dieldrin analogue indicated a structure-specific effect important for elucidating the mechanisms of dieldrin neurotoxicity.

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Section: ■ Discussionmentioning

confidence: 99%

Cellular Localization of Dieldrin and Structure–Activity Relationship of Dieldrin Analogues in Dopaminergic Cells

Allen

Florang

Davenport

et al. 2013

Chem. Res. Toxicol.

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“…The pentachloroketone (3) was reported to be more toxic than photodieldrin to mosquitoes and houseflies (Khan et al, (Continued) 1970) but less toxic and slower acting than PD to the German cockroach (Kadous and Matsumura, 1982;Reddy and Khan, 1977), indicating that PD itself is the active toxicant in this insect. PD acted fourfold more rapidly (LD 50 , 0.01 g/insect) than dieldrin (LD 50 , 0.05 g/insect) and twofold more rapidly than the pentachloroketone (LD 50 , 0.13 g/insect), observations that suggest it has pharmacokinetic properties more favorable for toxicity than the other compounds.…”

Section: Inhibitorsmentioning

confidence: 99%

“…9-KEN is some fivefold more toxic than endrin to rats and appears to be the ultimate toxic metabolite of endrin (Bedford et al, 1975a;Hutson et al, 1975). Species differences are evident, since Kadous and Matsumura (1982) reported the order of endrin metabolite toxicity to male German cockroaches as 5-OH anti-9-OH 9-keto-, whereas the order on topical application was 9-keto  syn-9-OH  endrin » anti-9-OH to houseflies and 9-syn-OH  9-keto- endrin » anti-9-OH to blowflies (Brooks and Mace, 1987). Also in this report, syn-9-hydroxydieldrin (9-HD; 4) was essentially nontoxic to houseflies and blowflies, whereas the order 9-oxadieldrin (9-OD; 13, Figure 96.1)  dieldrin  9-ketodieldrin (9-KD; 8, Figure 96.3) and 9-oxadieldrin (9-OD)  9-KD  dieldrin, respectively, was found for houseflies and blowflies.…”

Section: Inhibitorsmentioning

confidence: 99%

“…Consequently, the alpha-isomer might be expected to be intrinsically at least as effective as the beta-isomer in terms of their interactions with the resistance-modified binding site, regardless of possible oxidation to the sulfate in vivo. In the case of endrin, the 9-keto-(12-keto-) metabolite is presumed to be the ultimate toxicant in mammals (Hutson et al, 1975) and may contribute to endrin toxicity in insects (Kadous and Matsumura, 1982); notably, this oxidation places a second, additional, electronegative center at D, near the upper subsite S (Figure 96.13), which may improve binding potency toward the resistance-modified binding site.…”

Section: Molecular Toxicology Of Noncompetitive Chloride Ionophore Blmentioning

confidence: 99%

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Interactions with the Gamma-Aminobutyric Acid A-Receptor

Brooks¹

2010

Hayes' Handbook of Pesticide Toxicology

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“…Cis aldrin diol is a metabolite of dieldrin that can then be epimerized to the trans diol in mammals(219). It was found not be as toxic in insects as dieldrin(220). Due to the environmental and metabolic relevancy, aldrin and cis aldrin diol were chosen for this study.…”

mentioning

confidence: 99%

Mechanisms of Toxicity and the Structure-Activity Relationships of Molinate and Dieldrin

Allen¹

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Pesticides have been used to control various types of pests, including plants and insects, for thousands of years, however the impact of exposure to these toxic chemicals, with respect to environmental and health consequences, is not fully understood. Two pesticides of interest, molinate and dieldrin, have been shown to cause neurotoxicity in humans, but their mechanisms of toxicity are still unknown. In order to better understand how exposure to these chemicals can cause toxicity, the structure-activity relationship (SAR) was defined to determine how specific changes to the structure of each pesticide affects the toxicity profiles of each of these compounds. Results of this study demonstrated that oxidation of molinate to molinate sulfoxide, and then further to molinate sulfone, a more potent inhibitor of aldehyde dehydrogenase. The sulfone metabolite is capable of covalently modifying the active-site cysteine residue of aldehyde dehydrogenase, accounting for the observed enzyme inhibition. These results indicate that the compound responsible for the toxicity from molinate exposure is not the parent compound, but rather one of the sulfoxidation metabolites. When the SAR of dieldrin was investigated with respect to a Parkinson's disease model, it was determined that the compounds that were previously found to be the least potent insecticides were the most toxic with respect to dopaminergic cells. Each of the compounds tested was observed to disrupt dopamine metabolism in accordance with their toxicity profiles in dopaminergic cells. In combination, these results implicate important structural features responsible for the toxicity with respect to Parkinson's disease. This information is critical for the development of new pesticides, and will be important to increase the selective toxicity for insects while minimizing adverse/off-target effects. This can lead to the development of safer, more effective pesticides that will be essential for future environmental and human health.

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Toxicity of metabolites of dieldrin, photodieldrin, and endrin in the cockroach

Cited by 8 publications

References 19 publications

Cellular Localization of Dieldrin and Structure–Activity Relationship of Dieldrin Analogues in Dopaminergic Cells

Cellular Localization of Dieldrin and Structure–Activity Relationship of Dieldrin Analogues in Dopaminergic Cells

Interactions with the Gamma-Aminobutyric Acid A-Receptor

Mechanisms of Toxicity and the Structure-Activity Relationships of Molinate and Dieldrin

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