Induction of peroxisomal beta-oxidation in the rat liver in vivo and in vitro by tetrazole-substituted acetophenones: structure-activity relationships.
LY171883, a leukotriene D4 antagonist in the tetrazole-substituted acetophenone structural class, previously was demonstrated to cause peroxisome proliferation in rodents. In the present studies, several analogs were tested to determine if there are structural requirements for the induction of peroxisomal beta-oxidation in the rat liver in vivo and in cultured rat hepatocytes. Liver weight and serum triglycerides also were measured in vivo. The increases in peroxisomal beta-oxidation caused by the tetrazole-substituted acetophenones in vivo ranged from negligible to greater than 17-fold and there was good agreement with the structure-activity relationships found in cultured hepatocytes. N-methylation of the acidic nitrogen of the tetrazole blocked the peroxisomal effects, indicating that the free acid was required for activity. The length of the alkyl chain linked to the tetrazole also influenced the activity of the compounds. However, the more important determinant of peroxisomal activity may be the spatial orientation of the acidic tetrazole with respect to the planar backbone of the molecule. The data indicate there is a target site for peroxisome proliferation in the liver that is able to distinguish between structurally similar analogs. This site appears to be distinct from the leukotriene receptor since both inducers and noninducers of peroxisomal beta-oxidation were shown previously to be potent leukotriene antagonists.
Eacho
P I
PI
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.
Foxworthy
P S
PS
Dillard
R D
RD
Whitesitt
C A
CA
Herron
D K
DK
Marshall
W S
WS
D000098:Acetophenones / Q000494:pharmacology*; D000284:Administration, Oral; D000818:Animals; D001393:Azoles / Q000494:pharmacology*; D001835:Body Weight / Q000187:drug effects; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008830:Microbodies / Q000187:drug effects* / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D010084:Oxidation-Reduction / Q000187:drug effects; D051381:Rats; D011916:Rats, Inbred F344; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000494:pharmacology*; D014280:Triglycerides / Q000097:blood
D000098:Acetophenones; D001393:Azoles; D013777:Tetrazoles; D014280:Triglycerides