Title : Hormonal and Chemical Regulation of Paraoxonases in Mice

In humans and rodents, Paraoxonase (PON/Pon) 1 expression and activity in livers and serum are higher in females than in males, and some drugs increase its expression. However, the underlining mechanisms of gender-divergent expression and chemical regulation of Pon1 remain largely unknown. The present study determined the regulatory mechanisms contributing to gender-divergent and chemically altered Pon expression in mouse livers. Pon1 mRNA was much more abundant in livers of mice than other tissues, with higher levels in female livers than males at mRNA and protein levels. Pon2 mRNA was ubiquitously expressed in mouse tissues, but minimally in mouse liver. Pon3 mRNA was most abundant in mouse lung and liver, and less abundant in other tissues. Pon1 mRNA was lowest in fetal liver, markedly increased at parturition, and remained relatively constant thereafter. Pon2 and 3 mRNA are highly expressed in fetal liver, and decreased after birth. Male-pattern growth hormone administration in hypophysectomized and lit/lit mice decreased Pon1 expression. Sex hormones and female-pattern growth hormone administration had no effects on Pon1 expression, indicating the importance of male-pattern growth hormone in regulating Pon1. AhR, PXR, and Nrf2 activators had no effect on Pon1 mRNA. A CAR activator decreased Pon1 expression in WT, but not in the CAR-null mice. In conclusion, Pon1 mRNA is most abundant in adult mouse livers, whereas Pon2 and 3 mRNAs were most abundant in fetal mouse livers. Female-predominant Pon1 expression in mouse livers is due to inhibitory effects of male-pattern GH secretion, and CAR activation decreases Pon1 expression.