Chemical synthesis of dual-radiolabelled cyclandelate and its metabolism in rat hepatocytes and mouse J774 cells.
1. The chemical synthesis of 3,3,5-trimethyl[1-3H]cyclohexanol, 3,3,5-trimethyl[2,3-3H]cyclohexanol and 3,3,5-trimethyl[2,3-3H]cyclohexanyl[1-14C]mandelate (cyclandelate) are described. The ratio of 3H/14C radioactivity in the ester was 27:1. 2. Cultured rat hepatocytes accumulated trimethylcyclohexanol rapidly and excreted its glucuronide into the culture medium. Rat hepatocytes also accumulated cyclandelate rapidly, hydrolysing the ester and excreting trimethylcyclohexanol into the medium. This trimethylcyclohexanol then re-entered the cells and was converted to its glucuronide prior to excretion. 3. In contrast, no hydrolysis of cyclandelate was seen on incubation with J774 cells, a transformed mouse macrophage. 4. Similar differences in hydrolytic activity were seen with microsomal fractions prepared from rat liver and J774 cells. Hepatic microsomes caused a rapid hydrolysis of cyclandelate while no hydrolysis was detectable after incubations of over an hour with J774 microsomes. 5. This difference in hydrolytic activity may have important implications for the action of cyclandelate on cholesterol metabolism in extrahepatic tissues.
White
D A
DA
Department of Biochemistry, Queen's Medical Centre, Nottingham, UK.
Heffron
F
F
Miciak
A
A
Middleton
B
B
Knights
S
S
Knight
D
D
D000818:Animals; D002460:Cell Line; D055598:Chemical Phenomena; D002621:Chemistry; D003495:Cyclandelate / Q000378:metabolism*; D006868:Hydrolysis; D007700:Kinetics; D008264:Macrophages; D008333:Mandelic Acids / Q000378:metabolism*; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D051381:Rats
D008333:Mandelic Acids; D003495:Cyclandelate