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Research interests

This laboratory is involved in the following toxicological areas:

In the Project 1, our main interest is focused on the molecular mechanism whereby dioxins produce their reproductive and developmental toxicity. Accumulating evidence we provided suggests that dioxin-mediated damage to fetal steroidogenesis imprints exual immaturity which is continued until adult ages. We have also proven that the reduced expression of fetal gonadotropins such as luteinizing hormone and follicle-stimulating hormone is a pre-requisite for the defect in gonadal steroidogenesis. Current evidence has strongly suggested that dioxin induces histone deacetylases to silence the expression of fetal gonadotropin genes. The methodology how we can combat with TCDD-produced damage to next generations is also being investigated. Regarding this issue, we found that a-lipoic acid, an obligate cofactor for energy production, restores completely a dioxin-produced reduction in the formation of gonadotropins and sex-steroids.

[Representative articles for this project]
  1. Hattori, Y., et al., Biochem. Pharmacol., 154: 213-221 (2018).
  2. Koga, T., et al., PLoS ONE, 7, e40322 (2012).
  3. Takeda, T., et al., J. Biol. Chem., 287, 18440-18450 (2012).
  4. Takeda, T., et al., J. Pharmacol. Exp. Ther., 329, 1091-1099 (2009).
  5. Mutoh, J., et al., Endocrinology, 147, 927-936 (2006).

We are trying to establish a new concept in the Project 2. It is well known that drug-metabolizing enzymes play an important role in the detoxification and activation of foreign chemicals. Although different sorts of drug-metabolizing enzymes have long been considered to work separately, our studies have demonstrated that cytochrome P450 (representative phase I enzyme) binds to phase II enzymes such as UDP-glucuronosyltransferase. This association is functional interaction resulting in a change in the function of both enzymes. We have also provided evidence that UGT function is regulated by endo- and exo-genous substances. For example, ATP and fatty acyl-CoAs modulate UGT function at levels close to the physiological concentrations. From these lines of evidence, UGT function seems to be regulated by not only single nucleotide polymorphism but also multiple other mechanisms. It is, therefore, likely that a combination of these factors determine the UGT-related drug sensitivity of individuals.

[Representative articles for this project]
  1. Miyauchi, Y., et al., Mol. Pharmacol., 88: 800-812 (2015).
  2. Ishii, Y., et al., Drug Metab. Dispos., 42, 229-238 (2014).
  3. Ishii, Y., et al., Drug Metab. Dispos., 40, 2081-2089(2012).
  4. Takeda, S., et al., Mol. Pharmacol., 75, 956-964 (2009).
  5. Okamura, K., et al., Biochem. Biophys. Res. Commun., 345, 1649-1656 (2006).