Use of matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) to visualize and support interpretation of toxic effects of 4-hydroxyphenylpyruvate dioxygenase inhibitors in rat tissues.

Abstract

4-Hydroxyphenylpyruvate dioxygenase inhibitors (HPPDi) are mainly used as herbicides and for therapeutic use in genetic diseases of tyrosine catabolism. Their primary mechanism of action is the inhibition of the second enzyme of tyrosine catabolism, leading to an accumulation of this amino acid in blood and tissues. In this work, rats were administered diets with 1 ppm, 2 ppm, and 10 ppm of HPPD-inhibitor BCS-CR75391 for up to 28 days, and tyrosine levels were measured in blood and in selected organs using mass spectrometry combined with gas or liquid chromatography and analyzed spatially using mass spectrometry imaging (MSI). The highest tyrosine accumulation was recorded in the pancreas, followed by the eyes and the thyroid gland. Metabolomic profiling showed that other amino acids and metabolites of the citric acid cycle were influenced by the treatment. A metabolic adaptation was observed in the liver and kidney 28 days after the treatment, but not in other tissues analyzed. MSI of the thyroid gland seems to reveal an uneven accumulation of tyrosine in the tissue of rats following treatment with BCS-CR75391. Most interestingly, a significant accumulation of iodide was detected in the thyroid gland of all rats treated with the 4-hydroxyphenylpyruvate dioxygenase inhibitor. In addition, induced high tyrosine levels by a tyrosine-rich diet also provoke the accumulation of iodide in the thyroid gland. While the toxicological impact of these results needs to be further investigated, these results support the use of MSI as an innovative and powerful tool to support toxicological assessment.