Toxicology of Industrial Compounds

224 PEROXISOME PROLIFERATION
normally measured as lauric acid 12-hydroxylase (Sharma et al., 1988a, b;
Gibson, 1989). Peroxisome proliferators also markedly increase carnitine
acetyltransferase activity which is localised in peroxisomal, mitochondrial
and microsomal fractions (Ishii et al., 1980; Bieber et al., 1981). In rat liver
good correlations have been reported between the induction of
peroxisomal fatty acid β-oxidation and organelle proliferation and between
the induction of peroxisomal and microsomal fatty acid oxidising enzyme
activities (Lake et al., 1984a; Lin, 1987; Sharma et al., 1988a, b; Dirven et
al., 1992).
Several laboratories have demonstrated that the characteristics of
peroxisome proliferation in vivo may also be observed in vitro in primary
rat and mouse hepatocyte cultures. Indeed, hepatocyte cultures have been
employed for studying various aspects of peroxisome proliferation
including structureactivity relationships and species differences in response
(Gray et al., 1982; Elcombe, 1985; Bieri, 1993; Lake and Lewis, 1993;
Foxworthy and Eacho, 1994).
Rodent peroxisome proliferators
Many different classes of chemicals have been found to produce
peroxisome proliferation in the rat and mouse (Cohen and Grasso, 1981;
Reddy and Lalwani, 1983; Stott, 1988; Moody et al., 1991; Bentley et al.,
1993; Lake and Lewis, 1993). Classes of industrial chemicals include
plasticisers, chlorinated solvents (e.g. trichloroethylene, perchloroethylene),
chlorinated paraffins and other chemicals (e.g. perfluoro-n-octanoic acid).
Types of plasticisers known to produce peroxisome proliferation include
phthalate esters (e.g. di-(2-ethyl-hexyl)phthalate (DEHP), di-(isodecyl)
phthalate), adipate esters (e.g. di-(2-ethyl-hexyl)adipate (DEHA)) and other
compounds (e.g. tri-(2-ethylhexyl) trimellitate). Apart from industrial
chemicals other known rodent hepatic peroxisome proliferators include
herbicides, hypolipidaemic and other categories of therapeutic agents,
certain steroids, food flavours and natural products.
While peroxisome proliferators appear to be structurally diverse, at least
for some compounds, similarities in their three-dimensional structures have
been reported (Lake et al., 1988; Lake and Lewis, 1993). Many studies
have demonstrated structure-activity relationships for various classes of
peroxisome proliferators including industrial chemicals (Lake and Lewis,
1993). A characteristic feature of many, but not all, peroxisome
proliferators is the presence of an acidic function (Lake et al., 1988; Lock
et al., 1989). This acidic function is normally a carboxyl group, either
present as a free carboxyl group in the parent structure or one that is
unmasked by metabolism. Alternatively, the chemical may contain a
chemical grouping which is a bioisostere of a carboxyl group (Thornber,