Toxicology of Industrial Compounds

N.P.E.VERMEULEN ET AL. 25
intra- and inter-individual differences in GSH-conjugation and mercapturic
acid excretion. Factors causing these differences are sex, stress, diet, age,
enzyme induction and inhibition, pathology and genetic variability. Apart
from these factors the presence or absence of glutathione S-transferases
(GSTs) or GST activity in different persons is of special interest in relation
to urinary mercapturic acid excretion. The most intriguing factor known in
this context is the human genetic polymorphism of mu-class GSTs. The
GST isoenzyme µ is expressed only in approximately 60% of the human
population. Mu-class GST isoenzymes showed a high specific activity
towards for example styrene-7,8-oxide and benzo(a)pyrene-4,5dihydrodiol-4,5-oxide
and E- and Z-DCP. Genetic polymorphism of muclass
GSTs was postulated as a determinant in the excretion of the
mercapturic acids of Z- and E-DCP in occupationally exposed applicators.
However, between mu-class positive (n=9) and mu-class
Table 2.2 Urinary excretion levels, urinary ratios and half-lives of elimination of Zand
E-DCP mercapturic acids of mu-class positive and mu-class negative
individuals a
a Urinary excretion level represents the cumulative excretion of Z- and E-DCP-MA
in 0–36 h urine, corrected for the time weighted average 8-h exposure to Z- and E-
DCP. Values are expressed as means±SD for the number of individuals indicated in
parentheses.
b (mmol mercapturic acid)/(mmol DCP m −3 ).
c Z-DCP-MA/E-DCP-MA
d Half-life of elimination
negative (n=3) applicators, neither a difference in urinary half-lives of
elimination nor in cumulative excretion of both mercapturic acids of Zand
E-DCP was seen (Vos et al., 1991) (Table 2.2).
α-Bromoisovalerylurea,
a sedative and hypnotic drug, is a racemic drug
which is also metabolized by GSH-conjugation. It was proposed as a
model substrate to study the pharmacokinetics and stereoselectivity of GSHconjugation
in humans. Stereoselective mercapturic acid formation of Rand
S-α-bromoisovalerylurea was seen in in vitro studies with purified GST
isoenzymes and in vivo in rat and man. In humans, a pronounced
stereoselectivity in urinary mercapturic acid excretion was observed. Of an
oral dose of R- and S-α-bromoisovalerylurea, 22.5±4.3 and 5.7±1.6% was
excreted as mercapturic acid in 24 h, respectively. The half-lives of
elimination of both diastereoisomeric mercapturic acids were 1.5±0.4 and
3.1±1.3 h, respectively. Both the pharmacokinetics of α-bromoisovaleryl