The enzymatic hydrolysis-activation of the adriamycin cardioprotective agent (+)-1,2-bis(3,5-dioxopiperazinyl-1-yl)propane.
The cardioprotective agent ICRF-187 [(+)-1,2-bis(3,5-dioxopiperazinyl-1-yl)propane, ADR-529] has shown a great deal of promise against what may be an iron-based adriamycin-induced cardiotoxicity. ICRF-187 likely exerts its actions through its rings-opened hydrolysis product, which has a structure similar to EDTA and like-wise strongly binds metal ions. The 105,000g soluble supernatant fraction of homogenates of porcine liver and kidney, but not of heart, enzymatically caused a ring-opening hydrolysis of ICRF-187 at the rate of 1.2, 1.4, and less than 0.15 nmol.(mg protein)-1.min-1, respectively. This enzymatic hydrolysis of ICRF-187 was completely abolished by 4-chlorobenzenesulfonamide, which suggested that dihydropyrimidine amidohydrolase (DHPase) might be, in large part, responsible for the ICRF-187 hydrolase activity. Bovine liver DHPase was isolated and was shown to enzymatically hydrolyze ICRF-187 with a Vmax of 14,900 nmol.(mg DHPase)-1.min-1, a value that exceeded that of its natural substrates. The KM for ICRF-187 of 6.7 mM was, however, much larger than that of its natural substrates. The enzyme kinetics were consistent with DHPase acting on ICRF-187 to form one-ring-opened hydrolysis product only. Thus, DHPase is not able to act on the one-ring-opened hydrolysis product to produce two-ring-opened product. The Ki for 4-chlorobenzenesulfonamide inhibition of DHPase was measured to be 26 microM.
Hasinoff
B B
BB
Faculty of Pharmacy, University of Manitoba, Winnipeg, Canada.
Reinders
F X
FX
Clark
V
V
D000581:Amidohydrolases / Q000378:metabolism; D000818:Animals; D001711:Biotransformation; D002417:Cattle; D004317:Doxorubicin / Q000037:antagonists & inhibitors* / Q000633:toxicity; D006868:Hydrolysis; D066298:In Vitro Techniques; D007668:Kidney / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D011929:Razoxane / Q000378:metabolism*; D013552:Swine
D011929:Razoxane; D004317:Doxorubicin; D000581:Amidohydrolases; C020047:dihydropyrimidinase