Characterization of the pig nuclear receptor CAR and its role in boar taint

The boar taint phenotype is caused by an accumulation of androstenone and/or skatole in pig fat causing an off odour in the meat. The nuclear receptor CAR (Constitutive Active/Androstane Receptor) controls the metabolism of lipophilic compounds, such as hormones and drugs, by regulating the expression of phase I and phase II metabolic enzymes. CAR may also be involved in the regulation of the metabolism of boar taint compounds. This project identified and characterized pig CAR and determined that it was closely related to human CAR. The human CAR ligand 6-(4-chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime (CITCO) induced pig CAR transcriptional activation; further beta-dihydrotestosterone was identified as a potent repressor of pig CAR and human CAR. While 5, 16-Androstadien-3beta-ol, and 16 (5alpha)-Androsten-3beta-ol are physiologically relevant repressors of pig CAR. Treatment of pig primary hepatocytes with CITCO or phenytoin increased the expression of genes that are of interest in the development of boar taint. This includes 3beta-HSD, 3alpha-HSD, SULT2A1, UGT2B for androstenone metabolism and CYP2A6 and CYP2E1 for skatole metabolism. Comparing liver gene expression from high and low androstenone boars identified a 5.66-fold increase in 3beta-HSD mRNA transcript in low androstenone boars; this is a key enzyme in the metabolism of androstenone. The research presented here demonstrates that CAR can be repressed by testicular derived hormones and regulates the expression of androstenone and skatole metabolic genes. These findings support the hypothesis that nuclear receptor CAR is repressed by testicular hormones, causing decreased expression of genes involved with the metabolism of boar taint compounds, leading to the accumulation of androstenone and skatole.