THE TOXICITY AND MODE OF ACTION OF DIPHENYLAMINE PESTICIDES

SHAFI M NIZAMANI, Purdue University

Abstract

N,N-Diphenylamines and N-substituted N,N-diphenylamines have broad scale of activity as pesticides. Studies were conducted to determine the effects of a series of ring-substituted diphenylamines on mitochondrial oxidative phosphorylation in mice and insects and on the photosynthetic reactions of spinach chloroplasts so as to ascertain and compare the biochemical mechanism of toxic action of these compounds in plants and animals. Ring substituted diphenylamines with acidic NH groups showed all the requisite properties to be classified as uncouplers of oxidative phosphorylation in mouse liver and tobacco hornworm gut mitochondria. They increased state 4 respiration and ATPase activity and decreased the respiratory control index and ADP:O ratio in these mitochondria using glutamate as the substrate. At low concentrations (10 nM) the most active compounds uncoupled photophosphorylation in chloroplasts, while at comparable or somewhat higher concentrations (10-100 nM) they inhibited electron transport in photosystem II. Photosystem I electron transport was resistant to inhibition by these compounds. The uncoupling activity against mitochondrial oxidative phosphorylation or inhibitory effects on photosystem II electron transport of these compounds were positively correlated with the total electron withdrawing effect of the ring substituents particularly as reflected in their pKa values. Although certain diphenylamines such as TTDA (2,4-dinitro-2',4',6'-trichloro-6-trifluoromethyldiphenylamine) were among the most potent uncouplers yet reported with clear activity at 1-10 nM, the conversion of the NH bridge to N-methyl resulted in a complete loss of uncoupling activity against oxidative phosphorylation in mouse liver mitochondria and spinach chloroplasts. However, this tertiary diphenylamine like its parent (TTDA), was highly toxic to insects, mites and mammals, causing hypothermia, rapid rigor mortis and brain edema in mice. These compounds appear to act in the same way and this might be attributable to the metabolic release of TTDA in vivo by N-demethylation. In support of this idea, the toxicity of N-methyl TTDA to mice is delayed compared to TTDA and is antagonized by pretreatments with inhibitors of the mixed function oxidase system.

Degree

Ph.D.

Subject Area

Pharmacology|Entomology

COinS