Co-induction of cytochrome P4504A1 and peroxisome proliferation: a causal or casual relationship?
1. The hypothesis that xenobiotic induction of hepatic microsomal cytochrome P4504A1 and peroxisome proliferation are closely-related phenomena has been further investigated. 2. Five rat strains (Gunn, Fischer, Wistar, Long Evans and Sprague Dawley) were all susceptible to xenobiotic induction of both microsomal cytochrome P4504A1 and peroxisome proliferation, and no strain exhibited a dissociation of these phenomena. 3. In comparison to rat, the marmoset was substantially less susceptible to the above hepatic changes. 4. Induction of both cytochrome P4504A1 and peroxisome proliferation by a structural analogue of clofibrate (2-(4-(4-chlorophenyl)benzyloxy)-2-phenyl acetic acid) demonstrated stereochemical selectivity, in that the R(-)-isomer was a more potent inducer of both phenomena than the S(+)-antipode, with the racemic mixture exhibiting an intermediate potency. 5. Cycloheximide inhibition of clofibrate-dependent induction of acyl CoA mRNA, but not cytochrome P4504A1 mRNA has indicated a protein dependency for peroxisome proliferation, not inconsistent with participation of cytochrome P4504A1 in the biogenesis of peroxisome proliferation. 6. Taken collectively, the data described herein provide further evidence for a close linkage between xenobiotic induction of cytochrome P4504A1 and peroxisome proliferation, and possible molecular mechanisms inter-relating these two phenomena are discussed.
Gibson
G G
GG
University of Surrey, School of Biological Sciences, Molecular Toxicology Group, Guildford, UK.
D000818:Animals; D002144:Callithrix; D002455:Cell Division / Q000187:drug effects; D002994:Clofibrate / Q000494:pharmacology; D003513:Cycloheximide / Q000494:pharmacology; D042926:Cytochrome P-450 CYP4A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000187:drug effects; D003998:Dicarboxylic Acids / Q000378:metabolism; D004790:Enzyme Induction; D005227:Fatty Acids / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000648:ultrastructure; D008297:Male; D008830:Microbodies / Q000201:enzymology / Q000502:physiology*; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000187:drug effects; D010084:Oxidation-Reduction; D051381:Rats; D011916:Rats, Inbred F344; D011919:Rats, Inbred Strains; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D013045:Species Specificity; D013237:Stereoisomerism
D065607:Cytochrome P-450 Enzyme Inhibitors; D003998:Dicarboxylic Acids; D005227:Fatty Acids; D003577:Cytochrome P-450 Enzyme System; D003513:Cycloheximide; D006899:Mixed Function Oxygenases; D042926:Cytochrome P-450 CYP4A; D002994:Clofibrate