The carbodiimide product of diafenthiuron reacts covalently with two mitochondrial proteins, the FO-proteolipid and porin, and inhibits mitochondrial ATPase in vitro.
1992
Ruder F.J. | Kayser H.
The thiourea diafenthiuron (CGA 106630), a new insecticide/acaricide, is rapidly transformed by desulfuration to the carbodiimide CGA 140408 in the presence of sunlight and singlet oxygen. There is also evidence that this conversion takes place biologically in the target organism. Diafenthiuron is thus assumed to be a propesticide acting via its carbodiimide CGA 140408. CGA 140408 affects mitochondrial respiration at the coupling site in both rat liver and Calliphora flight muscle mitochondria in vitro. This inhibition was previously found to proceed in a time- and concentration-dependent manner. The present paper is concerned with the molecular mechanisms underlying this action. We show that the inhibition of the coupling site is paralleled by the block of F0/F1 ATPase activity. In its chemical reactivity, the carbodiimide CGA 140408 resembles dicyclohexylcarbodiimide (DCCD) in that both compounds inhibit ATPase activity, with pseudo-first order reaction constants of 0.025 (CGA 140408) and 0.020 (DCCD) per (nmol carbodiimide/mg protein) per min. Furthermore, both carbodiimides covalently bind to proteins. On incubation with Calliphora mitochondria in vitro, both [14C]DCCD and [14C]CGA 140408 label an 8-kDa protein, identified as the proteolipid of the F0 ATPase in the inner mitochondrial membrane, and a 32-kDa protein, the channel-forming porin of the outer mitochondrial membrane, as seen by fluorography of SDS polyacrylamide gets. In contrast, in rat liver mitochondria, [14C]CGA 140408 labels only the proteolipid, and not mitochondrial porin, while [14C]DCCD labels both, indicating that CGA 140408 reacts more selectively than DCCD in mammals. Whether the binding selectivity of CGA 140408 is related to its low mammalian toxicity is not yet known. These in vitro data suggest that the mode of action of CGA 140408 as the active product of diafenthiuron is correlated with its ability to bind covalently to proteins. Mitochondrial ATPase and porin are selective targets for this reaction. Several hypotheses concerning the mode of action are discussed, the focus being on partial or total disruption of mitochondrial activity.
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