Induction ofperoxisome proliferation andhepatic tumoursin C57BL/6Nmicebyciprofibrate, a hypolipidaemic compound

effect of ciprofibrate, a non-genotoxic chemical, indicate thatperoxisome proliferation can beusedas a reliable parameter toevaluate thecarcinogenicity ofhypolipidaemic compounds. Peroxisome proliferation isa unique phenomenon common toseveral structurally diverse chemicals including hypolipidaemicdrugs, phthalate esterplasticizers, industrial solvents andtetrazole substituted alkoxyacetophenone (Hessetal., 1965;Reddy& Krishnakantha, 1975;Moody& Reddy, 1978; Reddy& Lalwani, 1983; Elcombe etal., 1985; Eacho etal., 1986). Of thesechemicals, thebiological effects of hypolipidaemic drugsandphthalate esters havebeenextensively studied (Reddy& Lalwani, 1983; Reddyetal., 1982a; Cohen& Grasso, 1981; Lakeetal., 1984; Reddy& Rao, 1986; Rao& Reddy,1987). Theimmediate hepatic effects of these compounds arehepatomegaly secondary tohyperplasia andhypertrophy ofparenchymal cells andmarkedproliferation ofperoxisomes (Moodyetal., 1977; Reddyetal., 1979; Reddy& Lalwani, 1983; Gray& delaIglesia, 1984). Peroxisome proliferation isassociated witha disproportionate increase intheactivities ofseveral peroxisomal enzymes.Hydrogen peroxide generating enzymesofthefatty acidf-oxidation system areincreased byseveral fold, whereas catalase, theenzyme thatdegrades H202isinduced minimally and urateoxidase activity remainsunaltered (Lazarow & deDuve,1976;Hashimoto, 1982;Moody& Reddy,1978; Lakeetal., 1984; Reddyetal., 1986b; Usuda etal., 1988). Theseearly hepatic effects remain invariant as long asthehypolipidaemic compounds areadministered and regressas soon as thetreatment isdiscontinued (Moody& Reddy,1976;Miyazawaet al.,1980).Althoughthe magnitude of peroxisome proliferation isdifferent in different species, thehypolipidaemic compounds were shown toinduce peroxisomes inrodents, non-rodents andprimates (Gray& delaIglesia, 1984; Reddyetal., 1984; Lalwani et al., 1985). Theexactmechanismbywhichthestructurally diverse chemicals induceperoxisome proliferation isnot clear. Thepresent experimental evidence indicates thatthe hypolipidaemic compounds mostlikely actthrough a cytosolicreceptor-mediated mechanism(Lalwani etal., 1983; Reddy& Rao,1986; Lalwani etal., 1987). Anotherintriguing aspectofxenobiotics thatare associated withan increase inperoxisomes istheir hepatocarcinogenic property inratsandmice,despite their inability to interact withanddamageDNA (Warren etal., 1980; Gupta etal., 1985). Sincetheinitial observation ofthecarcinogenic effect ofnafenopin inacatalasemic micebyReddyandhis associates (1976), several hypolipidaemic compoundshave beenshowntoinduceliver tumours(Reddy& Rao,1977; Reddyetal., 1979; Svoboda& Azarnoff, 1979; Reddyetal., 1980; Lalwani etal., 1981; Rao etal., 1984; Kluweetal.,