Metabolic response to oral microcystin-LR exposure in the rat by NMR-based metabonomic study

Microcystin-LR (MCLR), a potent hepatotoxin, is causing increased risks to public health. Although the liver is the main target organ of MCLR, the metabolic profiling of liver in response to MCLR in vivo remains unknown. Here, we comprehensively analyzed the metabolic change of liver and ileal flushes in rat orally gavaged with MCLR by 1H nuclear magnetic resonance (NMR). Quantification of hepatic MCLR and its glutathione and cysteine conjugates by liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS) was conducted. Metabonomics results revealed significant associations of MCLR-induced disruption of hepatic metabolisms with inhibition of nutrient absorption, as evidenced by a severe decrease of 12 amino acids in the liver and their corresponding elevation in ileal flushes. The hepatic metabolism signature of MCLR was characterized by significant inhibition of tyrosine anabolism and catabolism, three disrupted pathways of choline metabolism, glutathione exhaustion, and disturbed nucleotide synthesis. Notably, substantial alterations of hepatic metabolism were observable even at the low MCLR-treated group (0.04 mg/kg MCLR), although no apparent histological changes in liver were observed in the low- and medium-dosed groups. These observations offered novel insights into the microcystin hepatotoxic mechanism at a functional level, thereby facilitating further assessment and clarification of human health risk from MCs exposure.