TY - JOUR T1 - Metabolism of 3,5,5-Trimethylhexanoyl-Ferrocene by Rat Liver: Release of Iron from 3,5,5-Trimethylhexanoyl-Ferrocene by a Microsomal, Phenobarbital-Inducible Cytochrome P-450 JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 255 LP - 260 VL - 27 IS - 2 AU - Edward E. Cable AU - Harriet C. Isom Y1 - 1999/02/01 UR - http://dmd.aspetjournals.org/content/27/2/255.abstract N2 - 3,5,5-Trimethylhexanoyl (TMH)-ferrocene has been used to produce iron loading in whole animals and in cultured hepatocytes. Iron loading produced by TMH-ferrocene is highly efficient and, of the compounds used to produce iron loading in experimental systems, most closely mimics the loading patterns observed in the human disease hemochromatosis. Previous work with TMH-ferrocene has shown that TMH-ferrocene is degraded in vivo because the iron is released from the ferrocene nucleus. Because TMH-ferrocene is highly lipophilic and stable chemically, we hypothesize that this molecule indeed could be degraded enzymatically. To measure the breakdown of TMH-ferrocene, iron release from the molecule was analyzed using a Ferrochem II analyzer, which uses constant potential coulometry to measure the amount of ionic iron within a biological sample. In this study, we show that TMH-ferrocene is degraded by a microsomal enzyme that requires NADPH and molecular oxygen. The TMH-ferrocenase activity is heat labile, requires a physiologic temperature, is induced by phenobarbital, and is inhibited by carbon monoxide and piperonyl butoxide but not by dicoumarol. The enzyme follows Michaelis–Menten kinetics and has aKm of 58.5 μM and aVmax of 57.5 nmol Fe released/mg protein/min. We conclude that TMH-ferrocene is degraded by a phenobarbital-inducible cytochrome P-450. The American Society for Pharmacology and Experimental Therapeutics ER -