Cytochrome P450IIE1 (CYP2E1) is induced by skatole and this induction is blocked by androstenone in isolated pig hepatocytes.
Skatole, a derivative of tryptophan, is produced in the hind-gut of pigs and is metabolised via hepatic cytochrome P4502E1 (CYP2E1). Excessive accumulation of skatole together with androstenone, a metabolite of testosterone, in adipose tissue in some pigs is a major cause of 'boar taint' and is associated with defective expression of CYP2E1. This phenomenon is not understood because factors regulating CYP2E1 expression in pig liver have not yet been characterised. Therefore effects of skatole and androstenone on CYP2E1 expression were studied using isolated pig hepatocytes as a model system. Skatole induced CYP2E1 protein expression to the same degree as did acetone, a known CYP2E1 inducer. Induction by skatole was maximum between 20 and 28 h and a half-maximum effect was obtained at a skatole concentration of 0.2 mM. Induction of CYP2E1 by skatole was protein-synthesis dependent. Androstenone antagonised the effect of skatole on CYP2E1 expression but did not affect the CYP2E1 protein level when added alone. These results suggest that defective expression of CYP2E1 in some pigs is due to excessive concentrations of androstenone which prevent CYP2E1 induction by its substrate skatole. As a result, skatole metabolism is reduced and skatole is accumulated in adipose tissue.
Doran
Elena
E
Department of Biochemistry, School of Medical Sciences, University of Bristol, University Walk, UK.
Whittington
Frances W
FW
Wood
Jeffrey D
JD
McGivan
John D
JD
D000273:Adipose Tissue / Q000201:enzymology; D000738:Androsterone / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D003513:Cycloheximide / Q000494:pharmacology; D019392:Cytochrome P-450 CYP2E1 / Q000096:biosynthesis*; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology*; D008297:Male; D012862:Skatole / Q000494:pharmacology*; D013552:Swine
D065691:Cytochrome P-450 CYP2E1 Inhibitors; D004791:Enzyme Inhibitors; D003513:Cycloheximide; D012862:Skatole; D000738:Androsterone; D019392:Cytochrome P-450 CYP2E1