RT Journal Article
SR Electronic
T1 THE ROLE OF CYP2A AND CYP2E1 IN THE METABOLISM OF 3-METHYLINDOLE IN PRIMARY CULTURED PORCINE HEPATOCYTES
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 848
OP 854
DO 10.1124/dmd.105.008128
VO 34
IS 5
A1 Michael A. Terner
A1 W. James Gilmore
A1 Yanping Lou
A1 E. James Squires
YR 2006
UL http://dmd.aspetjournals.org/content/34/5/848.abstract
AB The accumulation of 3-methylindole (3MI) in uncastrated male pigs (boars) is a major cause of boar taint, which negatively affects the quality of meat from the animal. Previously, CYP2E1 and CYP2A have been identified as cytochrome P450 (P450) isoforms involved in the metabolism of 3MI using porcine liver microsomes. This study further examines the role of these isoforms in the metabolism of 3MI using a primary porcine hepatocyte model by examining metabolic profiles of 3MI after incubation with P450 inhibitors. Incubation of hepatocytes with 4-methylpyrazole resulted in a selective inhibition of CYP2E1 activity as determined by p-nitrophenol hydroxylase activity and an associated significant decrease in the production of the 3MI metabolites 3-hydroxy-3-methyloxindole and 3-methyloxindole. Furthermore, inhibition of CYP2A, as assayed by coumarin 7-hydroxylase activity, using 8-methoxypsoralen and diethyldithiocarbamate was not associated with any further significant inhibition of the production of 3MI metabolites. Treatment with general P450 inhibitors resulted in further decreases in CYP2E1 activity and a more dramatic decrease in the production of 3MI metabolites, suggesting that additional P450s may be involved in the phase 1 metabolism of 3-methylindole. In conclusion, CYP2E1 activity levels are more important than CYP2A activity levels for the metabolism of 3-methylindole in isolated pig hepatocytes. The American Society for Pharmacology and Experimental Therapeutics