The human
aldose reductase, AKR1B1, participates in
glucose metabolism and osmoregulation and is supposed to play a protective role against toxic
aldehydes derived from lipid peroxidation and steroidogenesis that could affect cell growth/differentiation when accumulated. Adrenal gland is a major site of expression of AKR1B1, and we asked whether changes in its expression could be associated with adrenal disorders. Therefore, we examined AKR1B1 gene expression in human fetal adrenals, adrenocortical cell line, and
tumors and compared the results with the expression of steroidogenic genes (StAR and CYP11A) and regulators of adrenal cortex development [steroidogenic factor-1 (SF-1) and
dosage-sensitive sex reversal-adrenal hypoplasia congenita critical region on the X chromosome, gene 1 (DAX1)]. Using specific
antibodies, Northern blotting, and enzymatic assays, we present evidences that AKR1B1 detectable in 15-wk-old fetal glands is regulated by cAMP in NCI-H295 cells and thus that AKR1B1 is functionally related to the
ACTH-responsive murine akr1b7/mvdp gene rather than to its direct ortholog, the mouse
aldose reductase akr1b3 gene. Although low DAX1 expression in
aldosterone-producing
adenomas (n = 5) was confirmed (P < 0.05), no correlation was found between the expression of all other genes and the
tumors endocrine activity. In contrast, relative abundance of AKR1B1
mRNA was decreased in
adrenocortical carcinomas (n = 5; mean +/- sem, 0.95 +/- 0.2) when compared with
adenomas (n = 12; 9.29 +/- 3.05; P < 0.001). Most (seven of eight)
adrenocortical carcinomas (19.0 +/- 5.4) had very low relative AKR1B1
protein levels when compared with benign
tumors (
cortisol-producing
adenomas, n = 5, 63.0 +/- 9.8; nonfunctional
adenomas, n = 5, 58.0 +/- 10.4;
aldosterone-producing
adenomas, n = 4, 65.3 +/- 7.7; P < 0.001), Cushing's
hyperplasia (n = 5, 54.6 +/- 5.3; P < 0.01), or normal adrenals (n = 4; 37.1 +/- 5.3; P < 0.001). These properties provide the first evidence that expression of cAMP-regulated AKR1B1 is decreased in
adrenocortical cancer. This might take part in adrenal
tumorigenesis and could be investigated as a marker of
malignancy for the diagnosis of adrenal
tumors.