PEROXISOME PROLIFERATORS - PARADIGMS AND PROSPECTS

被引:33
作者
GIBSON, GG
机构
[1] Molecular Toxicology Group, School of Biological Sciences, University of Surrey, Guildford, Surrey
关键词
PEROXISOME PROLIFERATOR; CYTOCHROME-P4504; FAMILY; HEPATOCARCINOGENICITY; NONMUTAGENIC CARCINOGEN;
D O I
10.1016/0378-4274(93)90130-P
中图分类号
R99 [毒物学(毒理学)];
学科分类号
100405 ;
摘要
Peroxisome proliferators are a structurally diverse group of chemicals. They include fibrate hypolipidaemic drugs, phthalate ester plasticisers, phenoxy acid herbicides, azole antifungal drugs, and perfluorinated fatty acids. This presentation will focus on the common pleotropic responses produced by these compounds including hepatomegaly (hyperplasia and hypertrophy), activation of cell cycle S-phase ploidy changes, cytochrome P4504A1 induction, morphometric/biochemical analysis of peroxisome proliferation and stimulation of growth factors, and oncogene activation. Consideration will also be given to the role of recently described Peroxisome Proliferator Activated Receptor in these diverse hepatic responses. Peroxisome proliferators are uniformly negative in a wide range of genotoxicity tests, but nevertheless are complete carcinogens, particularly in rodent liver. Mechanisms of nonmutagenic carcinogenesis will be discussed including the active oxygen hypothesis involving 8-hydroxydeoxyguanosine adducts and the possibility of peroxisome proliferators promoting preexisting lesions by clonal expansion, eventually resulting in frank tumorigenesis. Finally, a consideration of the risk assessment of peroxisome proliferation to humans will be discussed.
引用
收藏
页码:193 / 201
页数:9
相关论文
共 21 条
[1]   INFLUENCE OF FENOFIBRATE ON CELLULAR AND SUBCELLULAR LIVER STRUCTURE IN HYPERLIPIDEMIC PATIENTS [J].
BLUMCKE, S ;
SCHWARTZKOPFF, W ;
LOBECK, H ;
EDMONDSON, NA ;
PRENTICE, DE ;
BLANE, GF .
ATHEROSCLEROSIS, 1983, 46 (01) :105-116
[2]  
BRONFMAN M, 1989, BIOCHEM BIOPH RES CO, V159, P1023
[3]  
CATTLEY RC, 1989, CANCER RES, V49, P3246
[4]   FAILURE OF THE PEROXISOME PROLIFERATOR WY-14,643 TO INITIATE GROWTH-SELECTABLE FOCI IN RAT-LIVER [J].
CATTLEY, RC ;
MARSMAN, DS ;
POPP, JA .
TOXICOLOGY, 1989, 56 (01) :1-7
[5]  
CHERKAOUIMALKI M, 1990, BIOCHEM BIOPH RES CO, V173, P855
[6]   PEROXISOME PROLIFERATION DUE TO DI(2-ETHYLHEXYL) PHTHALATE (DEHP) - SPECIES-DIFFERENCES AND POSSIBLE MECHANISMS [J].
ELCOMBE, CR ;
MITCHELL, AM .
ENVIRONMENTAL HEALTH PERSPECTIVES, 1986, 70 :211-219
[7]   CYTOCHROME-P-450 INDUCTION BY CLOFIBRATE - PURIFICATION AND PROPERTIES OF A HEPATIC CYTOCHROME-P-450 RELATIVELY SPECIFIC FOR THE 12-HYDROXYLATION AND 11-HYDROXYLATION OF DODECANOIC ACID (LAURIC-ACID) [J].
GIBSON, GG ;
ORTON, TC ;
TAMBURINI, PP .
BIOCHEMICAL JOURNAL, 1982, 203 (01) :161-168
[8]  
GLAUERT HP, 1989, CANCER LETT, V43, P95
[9]   RECEPTOR-MEDIATED MECHANISMS OF PEROXISOME PROLIFERATORS [J].
GREEN, S .
BIOCHEMICAL PHARMACOLOGY, 1992, 43 (03) :393-401
[10]   RELATIONSHIP BETWEEN MORPHOLOGICAL-CHANGES AND LIPID-LOWERING ACTION OF PARA-CHLORPHENOXYISOBUTYRIC ACID (CPIB) ON HEPATIC MITOCHONDRIA AND PEROXISOMES IN MAN [J].
HANEFELD, M ;
KEMMER, C ;
KADNER, E .
ATHEROSCLEROSIS, 1983, 46 (02) :239-246