Toxicology of Industrial Compounds

17
Peroxisome Proliferation
BRIAN G.LAKE and ROGER J.PRICE
BIBRA International, Carshalton, Surrey
Introduction
Peroxisomes (sometimes referred to as ‘microbodies’) are single
membranelimited cytoplasmic organelles which are characterised by their
content of catalase and a number of hydrogen peroxide generating oxidase
enzymes (Cohen and Grasso, 1981; Reddy and Lalwani, 1983). In rat liver,
peroxisomes are normally spherical or oval in shape, approximately 0.5 µm
in diameter and contain a finely granular matrix with a crystalline nucleoid
core. A number of reviews have been published dealing with various
aspects of hepatic peroxisome proliferation (Cohen and Grasso, 1981;
Reddy and Lalwani, 1983; Hawkins et al., 1987; Stott, 1988; Lock et al.,
1989; Moody et al., 1991; Bentley et al., 1993; Lake, 1993). This chapter
will focus on mechanisms of hepatocarcinogenesis, species differences in
response and risk assessment of rodent peroxisome proliferators.
Peroxisome proliferation in rodent liver
Since the initial observations on the hepatic effects of the hypolipidaemic
agent clofibrate (Paget, 1963; Hess et al., 1965) many compounds have
been shown to produce hepatic peroxisome proliferation in rats and mice.
Liver enlargement is due to both hyperplasia and hypertrophy and
organelle proliferation is associated with a differential induction of
peroxisomal enzyme activities. Peroxisomes, like mitochondria, contain a
complete fatty acid β-oxidation cycle (Lazarow and DeDuve, 1976). While
the enzymes of the β-oxidation cycle (normally assessed as cyanideinsensitive
palmitoyl-CoA oxidation) are markedly induced, only small
changes are observed in other peroxisomal enzyme activities such as
catalase and D-amino acid oxidase. Apart from stimulating peroxisomal
fatty acid metabolism, peroxisome proliferators also increase microsomal
fatty acid ( -l)- and particularly -hydroxylase activities. This is due to
induction of cytochrome P-450 isoenzymes in the CYP4A subfamily and is