Regulation of 3‐methylindole metabolism by nuclear receptors

Regulation of 3‐methylindole metabolism by nuclear receptors 3‐methylindole (3MI) is a known pneumotoxin that is found in naturally in fecal matter and is a major component of tobacco smoke; it is also a major component of boar taint, the accumulation of malodorous compounds in pigs that negatively impacts meat quality. We studied the effects transactivation of the constitutive androstane receptor (CAR), pregnane X receptor (PXR), and farnesoid X receptor (FXR) on gene expression and the metabolism of 3MI in porcine hepatocytes. Real‐time PCR was used to determine the expression of key genes in agonist treated porcine hepatocytes, while the production of major 3MI metabolites over time was quantified by HPLC. FXR transactivation significantly (p<0.05) increased the expression of CYP2E1, which is crucial to 3MI metabolism, 1.29 (1.19,1.40) fold over the untreated controls. PXR transactivation increased CYP2A19 expression 1.24 (1.14, 1.36) and CYP2C49 expression 4.51 (3.64, 5.57) fold; both of these enzymes have been shown to play a role in 3MI metabolism in pigs. FXR transactivation stimulated the formation of 6‐hydroxy‐3‐methylindole, a metabolite crucial in the 3MI excretion pathway, by 1.86 fold over the untreated controls. CAR and PXR transactivation did not affect overall 3MI metabolism or the formation of major metabolites. FXR may thus play an important role in regulating the excretion of 3MI, thus helping prevent toxicity, as well as improving meat quality in boars.