Toxicology of Industrial Compounds

existence of a large number of isoenzymes with different, though
overlapping, substrate selectivity. The final detoxification capacity through
GSH and GST enzymes of an organism depends on endogenous factors
such as tissue distribution, genetic deficiencies, aging and hormonal
influences and on exogenous factors such as sensitivity to inhibition and
induction of GSTs (Vermeulen, 1989; Van Welie et al., 1992).
GSH-conjugates normally are not excreted unchanged in urine or faeces.
Catabolism of the GSH-conjugates results in the formation and excretion
of a variety of sulphur containing metabolites, among which thioethers and
mercapturic acids (S-substituted N-acetyl-cysteine conjugates) belong to the
most important. The mercapturic acid pathway is shown in Figure 2.6.
Thioethers in human studies
N.P.E.VERMEULEN ET AL. 21
Figure 2.6 Schematic representation of the mercapturic acid pathway: GSHconjugation
with an electrophilic chemical (RX) and the biosynthesis to a
mercapturic acid. E1: glutathione S-transferase, E2: -glutamyltranspeptidase, E3:
cysteinylglycinase and aminopeptidase, E4: cysteine conjugate N-acetyltransferase,
E5: N-deacetylase.
Several years ago, Seutter-Berlage et al. proposed the appearance of
thioethers such as mercapturic acids (R-S-R′), mercaptans (R-SH) and
disulfides (R-S-S-R′) in urine as an indicator of exposure to potentially
alkylating chemicals. The thioether assay is an aselective assay to detect
metabolic end-products excreted in urine of (non)occupational exposure to
various electrophilic chemicals. It includes three steps, namely: (i)
extraction, (ii) alkaline hydrolysis and (iii) derivatization, subsequently
followed by spectrophotometric analysis at 412 nm. The thioether assay