TARGETED OVEREXPRESSION OF ANDROGEN RECEPTOR WITH A LIVER-SPECIFIC PROMOTER IN TRANSGENIC MICE

The rodent liver displays marked age- and sex-dependent changes in and rogen sensitivity due to the sexually dimorphic and temporally program med expression of the androgen receptor (AR) gene. We have altered thi s normal phenotype by constitutive overexpression of the rat AR transg ene in the mouse liver by targeting it via the human phenylalanine hyd roxylase (hPAH) gene promoter. These transgenic animals in their heter ozygous state produce an approximate to 30-fold higher level of the AR in the liver as compared with the nontransgenic control, Androgen ina ctivation via sulfonation of the hormone by dehydroepiandrosterone sul fotransferase (DST), an androgen repressible enzyme, also contributes to the age- and sex-dependent regulation of hepatic androgen sensitivi ty. DST has a broad range of substrate specificity and is responsible for the age- and sex-specific activation of certain polycyclic aromati c hepatocarcinogens as well, by converting them to electrophilic sulfo nated derivatives. In the transgenic female, the hepatic expression of DST was approximate to 4-fold lower than in normal females, a level c omparable to that in normal males. The hPAH-AR mice will serve as a va luable model for studying the sex- and age-invariant expression of liv er-specific genes, particularly those involved in the activation of en vironmental hepatocarcinogens such as the aromatic hydrocarbons.