Dehydroepiandrosterone (
DHEA) is a peroxisome proliferating agent when administered in pharmacological dosages, but it has not been shown to function through the
peroxisome proliferator-activated receptor in cell-based assays. Because members of the
thyroid hormone/
vitamins A and D
nuclear receptor subfamily, including
PPAR, are known to modulate each other's function in gene expression by heterodimerization, we sought to establish whether
DHEA and
thyroid hormone interact to regulate several of the hepatic and renal
enzymes associated with peroxisome proliferation, i.e., peroxisomal beta-oxidation and microsomal
NADPH:cytochrome P450 oxidoreductase and the
cytochromes P450 4A. In rats administered exogenous T3 to attain a
hyperthyroid state, induction of the three
isozymes of
CYP4A (4A1, 4A2, and 4A3) by
DHEA was suppressed > 60-80% at the
mRNA level, with induction of
CYP4A2 mRNA being completely inhibited. Nuclear run-on transcription assays indicated that this inhibitory effect was regulated at the level of transcription. Induction of hepatic peroxisomal beta-oxidation by
DHEA or the peroxisome proliferator
nafenopin was in large part unaffected by treatment of animals with T3 under any condition tested. Microsomal
NADPH:cytochrome P450 oxidoreductase activity was induced by either
DHEA or T3; cotreatment resulted in an additive induction. When animals were treated with a lower dose of exogenous T3 that rendered the animals slightly
hyperthyroid, only induction of hepatic
CYP4A2 mRNA by
DHEA or
nafenopin was significantly inhibited (> 80%) compared with euthyroid control animals. Animals that had been rendered hypothyroid through removal of the thyroid gland showed normal induction of
CYP4A genes by
DHEA in liver, suggesting that their induction by
DHEA was not dependent on the presence of
thyroid hormone. The administration of exogenous T3 to thyroidectomized rats in the presence of
DHEA potently suppressed hepatic induction of all three genes at the
mRNA and
protein level. In experiments with cultured rat hepatocytes, physiological concentrations of T3 potently inhibited the induction of
CYP4A2 mRNA levels by
nafenopin but had little effect on induction of CYP4A1 or 4A3
mRNA. At higher T3 concentrations, the induction of CYP4A1/4A3
mRNA and
protein was also inhibited. These results suggest that T3 modulates the expression of
CYP4A2 at the level of transcription in physiologically relevant concentrations but that
hyperthyroid conditions are required to suppress expression of CYP4A1/4A3 genes. In euthyroid rodent kidney, which only expresses
CYP4A2 under either basal or
DHEA-induced conditions, near-physiological levels of T3 caused potent suppression of peroxisome proliferator-dependent induction of
CYP4A2 mRNA levels by either
DHEA or
nafenopin. In thyroidectomized rats, basal expression of
CYP4A2 mRNA was decreased relative to euthyroid controls, but
DHEA was as effective an inducer of this
mRNA as it is in euthyroid rats. As seen in euthyroid rats, T3 administration potently suppressed
DHEA induction of
CYP4A2 mRNA levels under either basal or induced conditions. Although
CYP4A expression was not derepressed in liver or kidneys of hypothyroid animals, our results indicated that the thyroid status of the animal did affect basal expression of
CYP4A2, suggesting involvement of
thyroid hormone or some other factor regulated by the thyroid gland on its constitutive expression.