Kinetics of the metabolic effects, distribution spaces and lipid-bilayer affinities of the organo-chlorinated herbicides 2,4-D and picloram in the liver.

Tordon® is the commercial name of a mixture of two organo-chlorinated herbicides, 2,4-D and picloram. Both compounds affect energy transduction in isolated mitochondria and the present study aimed at characterizing the actions of these two compounds on liver metabolism and their cellular distribution in the isolated perfused rat liver. 2,4-D, but not picloram, increased glycolysis in the range from 10 to 400 µM. The redox potential of the cytosolic NAD+-NADH couple was also increased by 2,4-D. Both compounds inhibited lactate gluconeogenesis. Inhibitions by 2,4-D and picloram were incomplete, reaching maximally 46% and 23%, respectively. Both compounds diminished the cellular ATP levels. No synergism between the actions of 2,4-D and picloram was detected. Biotransformations of 2,4-D and picloram were slow, but their distributions occurred at high rates and were concentrative. Molecular dynamics simulations revealed that 2,4-D presented low affinity for the hydrophobic lipid bilayers, the opposite occurring with picloram. Inhibition of energy metabolism is possibly a relevant component of the toxicity of 2,4-D and of the commercial product Tordon®. Furthermore, the interactions of 2,4-D with the membrane lipid bilayer can be highly destructive and might equally be related to its cellular toxicity at high concentrations.

The food additive BHA modifies energy metabolism in the perfused rat liver.

A study of the effects of butylated hydroxyanisole (BHA) on the hepatic metabolism was conducted with emphasis on parameters linked to energy metabolism and mitochondrial reactive oxygen species production. The experimental systems were the isolated perfused rat liver and isolated mitochondria. It was found that BHA inhibits biosynthetic pathways (gluconeogenesis) and ammonia detoxification, which are dependent on ATP generated within the mitochondria. Conversely, the compound stimulated glycolysis and fructolysis, which are compensatory phenomena for an inhibited mitochondrial ATP generation. Furthermore, BHA diminished the cellular ATP content under conditions where the mitochondrial respiratory chain was the only source of this compound. Inhibition of gluconeogenesis started at the concentration of 50 µM and was generally pronounced at concentrations under 200 µM. Several effects, however, were prominent only at the concentrations of 500 and 750 µM. BHA can be considered, thus, a mild metabolic agent that becomes toxic only at high doses. An aggravating factor could be the observation that BHA exerts a net stimulating action on reactive oxygen species (ROS) production in isolated mitochondria, an observation that contradicts the general notion that the compound acts primarily as an antioxidant. Considerable time was required for the reversion of most effects after removal of the compound from the circulation. In toxicological terms, besides the lack of circulating glucose, one can expect metabolic acidosis due to excess lactate production, impairment of ammonia detoxification and cell damage due to a deficient maintenance of its homeostasis and possible excessive ROS production.