Microcystins are a family of toxins produced by cyanobacteria found throughout the world in marine and freshwater environments. The most commonly encountered form of microcystin is microcystin-LR (MC-LR). Humans are exposed to MC-LR by drinking contaminated water. The toxin accumulates rapidly in the liver where it exerts most of its damage. Treatment of water containing MC-LR by ultrasonic irradiation leads to the breakdown of the toxin. Both the parent toxin and the treated toxin reaction products (TTRP) were evaluated for toxic effects in mice. Animals were exposed to purified MC-LR or an equivalent dose of the TTRP and sacrificed after 4 h or 24 h. Serum was collected and assayed for lactate dehydrogenase (LDH) activity as an indicator of hepatotoxicity. LDH activity was detected in the serum of MC-LR exposed mice indicative of liver damage, but not in control mice. Only a fraction of that activity was detectable in mice exposed to TTRP. Liver RNA was used for microarray analysis and real-time PCR. Individual animals varied in their overall genomic response to the toxin; however, only 20 genes showed consistent changes in expression. These include chaperones which may be part of a generalized stress response; cytochrome P450 which may be involved in metabolizing the toxin; and lipid dystrophy genes such as lipin-2, uridine phosphorylase and a homolog to tribbles, a stress-inducible gene involved in cell death. Of the genes that responded to the MC-LR, none showed significant changes in expression profile in response to TTRP. Taken together, the data indicate that ultrasonic irradiation of MC-LR effectively reduces hepatotoxicity in mice and therefore may be a useful method for detoxification of drinking water.