Urinary excretion glutathione conjugates

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. 

Urinary metabolites recovered within the first 16 h and representing 80% of the excretion products resulted from an initial methylation of cysteine residues by methyl methanesulfonate. These were mcthylmercapturic acid sulfoxide, 2-hydroxy-3-methyl-sulfmylpropionic acid, methylsulfmylacetic acid, methylmercapturic acid and 7V-(methyl-thioacetyl)glycine. Glutathione conjugation has been shown to occur in rat liver (lARC, 1974). 

DBCP is well absorbed by any route of exposure. Absorption is almost complete following oral exposure. Microsomal transformation leads to the formation of reactive metabolites. Metabolites undergo conjugation with glutathione. DBCP induces microsomal enzymes in the testes, liver, and kidneys. Covalently bound metabolites accumulate in the liver and kidneys. Urinary excretion is the major route of elimination. 

Polhuijs, M. te Koppele, J.M. Fockens, E. Mulder, G.J. Glutathione conjugation of the alpha-bromoisovaleric acid enantiomers in the rat in vivo and its stereoselectivity. Pharmacokinetics of bUiary and urinary excretion of the glutathione conjugate and the mercapturate. Biochem. Pharmacol. 1989, 38,... 

TTCA glutathione conjugate of carbon disulfide. Urinary TTCA excretion reliable indicator of exposure... 

The metabolism of vinyl chloride has recently been reviewed (130, 132, 218, 376). The major route of elimination of vinyl chloride after oral, intraperitoneal, or intravenous administration is by pulmonary excretion. The postulated metabolic pathway of vinyl chloride in vivo is illustrated in Fig. 19. The major urinary metabolites arise by conjugation with glutathione which is an important factor in the detoxification of vinyl chloride (759, 371). While one of the reac-... 

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