Peroxisome induction potential and lipid-regulating activity in rats. Quantitative microscopy and chemical structure-activity relationships.
Structurally diverse lipid-regulating agents induce hepatomegaly, hepatic peroxisome proliferation, and hepatocarcinoma in rats by mechanisms not fully understood. Nevertheless the initial hepatic response is a prompt, florid proliferation of peroxisomes. In investigations reported here, changes in the rat hepatic peroxisome compartment were measured by quantitative microscopy to determine chemical structure requirements that relate to peroxisome proliferation and lipid regulation. Aryloxyalkanoic acids plus amide analogs, and thio, benzimidazole, phenylpiperazine, and oxazole derivatives induced peroxisome proliferation and generally decreased plasma triglyceride and total cholesterol levels. These compounds contain an acidic function or are readily metabolized to a chemical with an acidic function. Substitution of the acidic function with an adamantyloxy eliminated peroxisome proliferation and induced contrasting effects on lipid profile, increasing triglycerides and decreasing total cholesterol. A previously unreported, direct correlation emerged between peroxisome proliferation and plasma high-density lipoprotein-cholesterol levels. These effects could not be elicited separately, negating identification of functional groups that could be associated with either activity. Chemical structure and resulting peroxisome proliferation with changes in plasma lipoproteins are therefore closely interrelated in rats.
McGuire
E J
EJ
Department of Pathology and Experimental Toxicology, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, MI 48105.
Lucas
J A
JA
Gray
R H
RH
de la Iglesia
F A
FA
D000577:Amides / Q000494:pharmacology; D000818:Animals; D001629:Bezafibrate / Q000494:pharmacology; D015248:Gemfibrozil / Q000031:analogs & derivatives* / Q000494:pharmacology; D008055:Lipids / Q000737:chemistry / Q000502:physiology*; D008074:Lipoproteins / Q000737:chemistry / Q000378:metabolism; D008099:Liver / Q000033:anatomy & histology / Q000166:cytology; D008830:Microbodies / Q000187:drug effects / Q000502:physiology*; D009929:Organ Size; D011422:Propionates / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
D000577:Amides; D008055:Lipids; D008074:Lipoproteins; D011422:Propionates; D015248:Gemfibrozil; D001629:Bezafibrate