In this critical review, I would like to provide a brief outline of the morphology, biochemical composition, distribution, and functions of peroxisomes. The induction of peroxisome proliferation and peroxisome-associated enzymes in the rodent liver by two classes of chemicals (hypolipidemic drugs and the industrial plasticizers) will be considered. The role of peroxisomes in lipid metabolism will be discussed. Carcinogenicity studies in rats and mice with these peroxisome proliferators will be evaluated critically. Careful consideration will be given to the hypothesis that "potent hepatic peroxisome proliferators as a class are carcinogenic." The possible mechanism(s) by which peroxisome proliferators induce liver tumors will be outlined. Particular attention will be paid to the possible role of peroxisome proliferation-mediated radical toxicity and generation of endogenous initiators of carcinogenesis.

Fatty acid beta-oxidation occurs in both mitochondria and peroxisomes. Mitochondria catalyze the beta-oxidation of the bulk of short-, medium-, and long-chain fatty acids derived from diet, and this pathway constitutes the major process by which fatty acids are oxidized to generate energy. Peroxisomes are involved, preferentially, in the beta-oxidation chain shortening of very long chain fatty acids (VLCFAs) and in the process produce H2O2. Long-chain fatty acids and VLCFAs are also metabolized by the cytochrome P450 CYP4A omega-oxidation system to toxic dicarboxylic acids (DCAs) that serve as substrates for peroxisomal beta-oxidation, and this process also leads to the production of superoxide and H2O2. The genes encoding peroxisomal, microsomal, and certain mitochondrial fatty acid metabolizing enzymes in liver are transcriptionally regulated by peroxisome proliferator-activated receptor alpha (PPAR alpha). Deficiencies of the enzymes of peroxisomal beta-oxidation have been recognized as important causes of disease. Evidence from mice deficient in PPAR alpha (PPAR alpha-/-), deficient in peroxisomal fatty acyl-CoA oxidase (AOX-/-), the first enzyme of the classical beta-oxidation system, and deficient in both PPAR alpha and AOX (PPAR alpha-/-AOX-/-) points to the critical importance of PPAR alpha-inducible peroxisomal and microsomal oxidation systems that metabolize LCFAs and VLCFAs in the pathogenesis of nonalcoholic microvesicular hepatic steatosis and steatohepatitis. These and other mouse models should provide greater understanding of the molecular mechanism responsible for hepatic steatosis and steatohepatitis. Deficiency of AOX disrupts the oxidation of VLCFAs, DCAs, and other substrates leading to extensive microvesicular steatosis and steatohepatitis. Loss of this enzyme also causes sustained hyperactivation of PPAR alpha, leading to transcriptional up-regulation of PPAR alpha-regulated genes, indicating that unmetabolized substrates of AOX function as ligands of PPAR alpha. beta-Oxidation is the major process by which fatty acids are oxidized to generate energy, especially when glucose availability is low during periods of starvation. Mice deficient in PPAR alpha and those nullizygous for both PPAR alpha and AOX show a minimal steatotic phenotype under fed conditions but manifest an exaggerated steatotic response to fasting, indicating that defects in PPAR alpha-inducible fatty acid oxidation determine the severity of fatty liver phenotype to conditions reflecting energy-related stress.

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Fully differentiated and functionally specialized acinar cells of the rat pancreas are versatile and adaptable. Acinar cells can be stimulated to divide following administration of a mitogen or after inducing acinar cell necrosis. The degree of compensatory hyperplasia is dependent upon the extent of acinar cell necrosis. Type I injury (subtotal acinar cell necrosis) is followed by marked proliferation of acinar cells leading to complete restitution of the pancreas, whereas subsequent to type II injury (global acinar cell necrosis) there is no restitution of the pancreas because of lack of enough viable cells that have served as precursor cells. Associated with type II injury there is proliferation of ductular and periductular cells followed by the development of hepatocytes. In addition, during adverse conditions acinar cells undergo dedifferentiation and form pseudoductular structures. In rats, acinar tissue is a prime target for carcinogens. Transformed acinar cells form foci which are morphologically classified as acidophilic and basophilic lesions. Acidophilic foci which show increased cell proliferation progress to form nodules and acinar cell carcinomas.

The carcinogenic effect of 2,2'-dihydroxy-di-n-propylnitrosamine (DHPN) was examined in the primitive primate, tree shrew (Tupaia glis). DHPN was administered at a dose of 250 mg/kg body weight sc once a week for 80 weeks. Between 65 and 102 weeks, 8 of 9 males given DHPN (89%) and 11 of 14 females given DHPN (78%) developed pulmonary adenomas. In 2 DHPN-treated males, in addition to adenomas, bronchioalveolar carcinomas were observed. Transmission electron microscopic examination of pulmonary adenomas from 4 DHPN-treated animals showed that Clara cells were the main components of these tumors. In addition to pulmonary tumors, 9% of the DHPN-treated animals developed squamous cell carcinomas of the skin and hepatocellular carcinomas. None of the 6 controls, which received olive oil alone, developed any tumors.