Excretion glutathione conjugates

In terrestrial animals, the excreted products of PAHs are mainly conjugates formed from oxidative metabolites. These include glutathione conjugates of epoxides, and sulfate and glucuronide conjugates of phenols and diols. 

Suzuki, H., Sugiyama, Y., Excretion of GSSG and glutathione conjugates mediated by MRP1 and cMOAT/ MRP2, Semin. Liver Dis. 1998, 18, 359-376. 

Marchand DH, Remmel RP, Abdel-Monem MM. Biliary excretion of a glutathione conjugate of busulfan and 1,4-diiodobutane in the rat. Drug Metab Dispos 1988 16(1) 85—92. 

Figure 2.12 Metabolic activation by the liver of pyrrolizidine alkaloid to the toxic pyrrole (liver bound and highly toxic) and the glutathione conjugate (excretion metabolite).

Fig. 8.28 Structure of 6-chloro-4-0X0-10-propyl-4 H-pyrano[3,2-g]quino-line-2,8-dicarboxylate which, in contrast to many related compounds (chromone-carboxylates) lacking the chloroquinoline, is excreted as a glutathione conjugate.

The conversion of the glutathione conjugate to its cysteinyl derivative is mediated, at least in part, by enzymes in the intestinal epithelial cells. S-(Pentachlorobutadienyl)glutathione and S-(pentachlorobutadienyl)-L-cysteine are partially reabsorbed from the intestines and transported to the liver and subsequently to the body tissues (Gietl et al. 1991). Only a portion of the reabsorbed material is taken up by the liver for additional metabolism. When liver uptake of the glutathione conjugate was measured using perfused rat livers, the maximum uptake observed was 39% (Koob and Dekant 1992). A portion of this material was re-excreted in bile without any metabolic... 

Absorption, Distribution, Metabolism, and Excretion. Data are available on the pharmacokinetics of hexachlorobutadiene in animals by the oral route, but not in humans. There are no data in humans or animals on exposures to hexachlorobutadiene by the inhalation or dermal routes. Because of the key role of the liver in producing the metabolites which are responsible for the nephrotoxicity of this compound, knowledge of the pharmacokinetics of inhalation and dermal exposures would be valuable. Oral studies reported the presence of the enzymes responsible for the glutathione conjugation reaction and the subsequent formation of derivatives in the liver, intestines, and kidney. 

Figure 4.66 Metabolism of a cysteine conjugate by CS lyase (p-lyase). The cysteine conjugate is shown arising from a glutathione conjugate after biliary excretion. The thiol product, which may be toxic (see text) can also be methylated and further oxidized as shown.

Gaigas et al. (1995) have developed a physiological toxicokinetic model of acrylonitrile in rats which includes the behaviour of CEO. In-vitro kinetic studies of the metabolism of both acrylonitrile and CEO showed that epoxidation to CEO is saturable, while glutathione conjugation of acrylonitrile follows first-order kinetics. The model combines these kinetic parameters with tissue partition data to allow simulation of the urinary excretion of acrylonitrile metabolites and the fonnation of haemoglobin adducts (see below). The model has been further refined by Kedderis et al. (1996) to predict the behaviour of acrylonitrile and CEO after inhalation exposure to acrylonitrile. 

Burka et al. (1994) examined the effect of treatment of rats with phenobarbital and SKF-525A on the urinary metabolite profile of [2- - C]aciy lonitnle. Phenobarbital treatment increased the excretion of products attributed to the oxidation of acrylonitrile to CEO, while SKF-525A treatment enhanced the excretion of the mercapturic acid derived from the glutathione conjugation of acrylonitrile itself. 

The observation of excretion of mercapturates of chloroprene indicates that glutathione conjugation occurs in rats. 

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