Reducing effect of matrix metalloproteinase inhibitors on serum triacylglycerol in streptozotocin-induced diabetic rats and Zucker fa/fa rats.
In the course of the investigation of effects of newly synthesized matrix metalloproteinase inhibitors (MMPIs), FYK-1388, FYK-1352 and F61-1008, which have strong and broad matrix metalloproteinase (MMP) inhibitory activity, on wound healing in streptozotocin (STZ)-induced diabetic rats, strong reducing effects on serum triacylglycerol (TG) have been found. Namely, when examined using breaking wound strength as an index, MMPIs did not significantly facilitate wound healing in STZ-induced diabetic rats. Unexpectedly, however, the treatment of STZ-induced diabetic rats with MMPIs markedly lowered the serum level of TG without changing the blood glucose level. Among these compounds tested, FYK-1388 was the most effective, and the compound reduced serum concentrations of TG and cholesterol and levels of very low-density lipoprotein (VLDL)-TG and low density lipoprotein (LDL)-cholesterol in a dose-dependent manner. FYK-1388 did not affect serum levels of free fatty acids, high-density lipoprotein (HDL)-cholesterol, aspartate aminotransferase and alanine aminotransferase, mass of body fat, liver weights, and hepatic contents of TG and cholesterol. Moreover, treatment of Zucker fa/fa rats with FYK-1388 lowered serum levels of TG and cholesterol without changing blood levels of glucose and insulin. Since the structures of these MMPIs markedly differ from those of the hypotriglyceridemic drugs that are used clinically, it seems plausible that these MMPIs could be used as a new type of hypotriglyceridemic drug.
Research Institute, Daiichi Fine Chemical Co. Ltd., 530 Chokeiji, Takaoka, Toyama 933-8511, Japan.
Tadanori
T
Morikawa
Tomoaki
T
Toyama
Naomi
N
Kudo
Yoichi
Y
Kawashima
D000273:Adipose Tissue / Q000187:drug effects; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D001786:Blood Glucose / Q000378:metabolism; D050218:Body Fat Distribution; D002784:Cholesterol / Q000097:blood; D003921:Diabetes Mellitus, Experimental / Q000097:blood*; D005230:Fatty Acids, Nonesterified / Q000097:blood; D006146:Guanidines / Q000494:pharmacology; D006877:Hydroxamic Acids / Q000494:pharmacology; D000960:Hypolipidemic Agents; D008055:Lipids / Q000097:blood; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000097:blood; D011480:Protease Inhibitors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker; D013329:Structure-Activity Relationship; D014280:Triglycerides / Q000097:blood*; D014945:Wound Healing / Q000187:drug effects
D001786:Blood Glucose; C476604:FYK 1388; D005230:Fatty Acids, Nonesterified; D006146:Guanidines; D006877:Hydroxamic Acids; D000960:Hypolipidemic Agents; D008055:Lipids; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D014280:Triglycerides; D002784:Cholesterol; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D020782:Matrix Metalloproteinases