Drug Biotransformation and Toxicology

Role of glutathione transferase zeta in the metabolism of dichloroacetic acid.

Dichloroacetate is both an orphan drug, used to reverse the Warburg effect in cancer cells and to treat acquired and congenital lactic acidosis, and an environmental pollutant found in chlorinated drinking water.  The first step in metabolism of dichloroacetate is glutathione-dependent dehalogenation to glyoxylate, catalyzed by GSTZ1, an enzyme whose physiological function is in isomerization of tyrosine catabolites.   As well as the studying the biotransformation of dichloroacetate, we are interested in understanding the toxicological effects of exposure to this agent.

Selected publications

Li, W., James, M.O., MacKenzie, S., Liu, C., Calcutt, N.S. and Stacpoole, P.W.  Mitochondrion as a novel site of dichloroacetate biotransformation.  J. Pharmacol. Exp. Therap. 336: 1-8, 2011. PMID 20884751

Li, W., Gu, Y., James, M.O., Hines, R.N., Simpson, P. Langaee, T. and Stacpoole, P.W.  Prenatal and postnatal expression of glutathione transferase zeta 1 in human liver and the roles of haplotype and subject age in determining activity with dichloroacetate. Drug Metabolism and Disposition, 40, 232-239, 2012. PMID 22028317

Zhong, G., Li, W., Gu, Y., Langaee, T., Stacpoole, P.W. and James, M.O.  Chloride and other anions inhibit dichloroacetate-induced inactivation of human liver GSTZ1 in a haplotype-dependent manner.  Chemico-Biological Interactions, 215:33-39, 2014. PMID: 24632415

Effects of endocrine disruptors on steroid biotransformation and transport.

Research has shown that several xenobiotics can affect the biotransformation and transport of estradiol, estrone and other steroid hormones.  This may result in beneficial or adverse effects on the organism, depending on the pathway affected.

Selected publications  

James, MO, Li, W, Summerlot, D, Rowland-Faux, L. and Wood CE. Triclosan is a potent inhibitor of estradiol and estrone sulfonation in sheep placenta.  Environment International, 36: 942-949, 2010

James, M.O. and Ambadapadi, S.  Interactions of cytosolic sulfotransferases with xenobiotics.  Drug Metabolism Reviews, 45(4):401-414,2013. PMID: 24188364.

Ambadapadi, S., Wang, P.L., Palii, S., and James M.O.  Celecoxib influences steroid sulfonation catalyzed by human recombinant sulfotransferase 2A1  J. Steroid Biochem. Mol. Biol. 152, 101-113, 2015  PMID 25960318

Biotransformation and bioavailability of ingested xenobiotics.

The extent of uptake of ingested xenobiotics into the animal body is influenced by biotransformation in the intestine and liver, as well as transport across the intestinal cells and from liver to bile or blood. Intestinal and hepatic biotransformation may result in either the activation or conversely the detoxication of xenobiotics. Xenobiotics of interest include chemicals such as polycyclic aromatic hydrocarbons, polychlorinated biphenyls, organochlorine pesticides and their metabolites and other environmental chemicals.

Selected publications 

Stuchal, L. Kleinow, K.M., Stegeman, J.J. and James, M.O.  Demethylation of the pesticide methoxychlor in liver and intestine from untreated, methoxychlor-treated and 3-methylcholanthrene-treated channel catfish (Ictalurus punctatus): Evidence for roles of CYP1 and 3A family isozymes.  Drug Metab. Disp. 34: 932-938, 2006

Nyagode, B.A., Kleinow, K.M. and James, M.O.  Influence of co-exposure to benzo(a)pyrene on the biotransformation and elimination of 14C-methoxychlor in the channel catfish, Ictalurus punctatus.  Toxicological Sciences, 108:320-329, 2009.

James, M.O., Marth, C.J. and Rowland-Faux, L.  Slow O-demethylation of methyl triclosan to triclosan, which is rapidly glucuronidated and sulfonated in channel catfish liver and intestine.  Aquatic Toxicology 124-125: 72-82, 2012