Modulation of peroxisome proliferator-activated receptor-α activity by bile acids causes circadian changes in the intestinal expression of Octn1/Slc22a4 in mice.

In addition to their digestive actions, bile acids modulate gene expression by altering the activity of peroxisome proliferator-activated receptor-α (PPARα). The modulatory effects of bile acids have been shown to affect the expression of genes responsible for lipid metabolism as well as membrane transporters. Bile acids are secreted in response to food intake and accumulate in intestinal epithelial cells. In the present study, we identified soluble carrier protein family 22 member 4 (Slc22a4), encoding organic cation transporter novel type-1 (Octn1), as a PPARα-regulated gene and its intestinal expression exhibited circadian oscillations in a bile acid-dependent manner. Nocturnally active mice mainly consumed their food around the early dark phase, during which bile acids accumulated in intestinal epithelial cells. PPARα activated the intestinal expression of Slc22a4 mRNA during the light period, and protein levels of Octn1 peaked before the start of the dark phase. The bile acids that accumulated in intestinal epithelial cells suppressed the PPARα-mediated transactivation of Slc22a4 in the dark phase. The time-dependent suppression of PPARα-mediated transactivation by bile acids regulated oscillations in the intestinal expression of Octn1/Slc22a4 during the daily feeding cycle. The results of a pharmacokinetic analysis also revealed that oscillations in the expression of Octn1 caused dosing time-dependent differences in the intestinal absorption of gabapentin (2-[1-(aminomethyl)cyclohexyl]acetic acid). These results suggest a molecular clock-independent mechanism by which bile acid-regulated PPARα activity governs the circadian expression of intestinal organic cation transporters. This mechanism could also account for interindividual variations in the pharmacokinetics of drugs that are substrates of Octn1.

Comparison of protein phosphatase inhibitory activity and apparent toxicity of microcystins and related compounds.

Two metabolites of microcystin-LR glutathione conjugate and, microcystin-cysteine conjugate, as well as microcystin-RR (MCRR) are less toxic than microcystin-LR (MCLR). In the present study, we investigated why these compounds are weakly toxic in comparison with MCLR, as the reason is still unknown and no systematic study has so far been carried out for a clarification of this issue. Although they showed almost the same inhibitory activity against protein phosphatases 1 and 2A as MCLR in vitro, the apparent toxicity of these three compounds by intratracheal administration to mice decreased to about 1/12 the level of MCLR at 100microg/kg. An immunostaining study showed that these conjugates at a sublethal dose of 200microg/kg were prominently observed in the intestine and kidney, whereas effective accumulation and bleeding were not found in the liver in spite of the larger dosage. As an explanation for these results, there may be two possibilities. First, the transport system to the liver might not function well, and second, transported toxins may be effectively eliminated by an appropriate system such as the GS-X (ATP-dependent glutathione S-conjugate exported) pump. It was concluded that the inhibitory activity against protein phosphatases is not always related to the apparent LD(50) level, and that the appearance of toxicity by microcystins depends on the balance between accumulation and metabolism in the liver.