Product of side-chain cleavage of cholesterol, isocaproaldehyde, is an endogenous specific substrate of mouse vas deferens protein, an aldose reductase-like protein in adrenocortical cells

Citation
Am. Lefrancois-martinez et al., Product of side-chain cleavage of cholesterol, isocaproaldehyde, is an endogenous specific substrate of mouse vas deferens protein, an aldose reductase-like protein in adrenocortical cells, J BIOL CHEM, 274(46), 1999, pp. 32875-32880
Citations number
37
Categorie Soggetti
Biochemistry & Biophysics
Journal title
JOURNAL OF BIOLOGICAL CHEMISTRY
ISSN journal
00219258 → ACNP
Volume
274
Issue
46
Year of publication
1999
Pages
32875 - 32880
Database
ISI
SICI code
0021-9258(19991112)274:46<32875:POSCOC>2.0.ZU;2-V
Abstract
Mouse vas deferens protein (MVDP) is an aldose reductase-like protein that is highly expressed in the vas deferens and adrenal glands and whose physio logical functions were unknown, We hereby describe the enzymatic characteri stics of MVDP and its role in murine adrenocortical YI cells, The murine al dose reductase (AR) and MVDP cDNAs were expressed in bacteria to obtain rec ombinant proteins and to compare their enzymatic activities. Recombinant MV DP was functional and displayed kinetic properties distinct from those of m urine AR toward various substrates, a preference for NADH, and insensitivit y to AR inhibitors. For MVDP, isocaproaldehyde, a product of side-chain cle avage of cholesterol generated during steroidogenesis, is the best natural substrate identified so far, In Y1 cells, we found that NADH-linked isocapr oaldehyde reductase (ICR) activity was much higher than NADPH-linked ICR ac tivity and was not abolished by AR inhibitors. We demonstrate that in Y1 ce lls, forskolin-induced MVDP expression enhanced NADH-linked ICR activity by 5-6-fold, whereas no variation in ICR-linked NADPH activity was observed i n the same experiment. In cells stably transfected with MVDP antisense cDNA , NADH-linked ICR activity was abolished even in the presence of forskolin, and the isocaproaldehyde toxicity was increased compared with that of inta ct Y1 cells, as measured by isocaproaldehyde LD50. In Y1 cells transfected with MVDP antisense cDNA, forskolin-induced toxicity was abolished by amino glutethimide, These results indicate that in adrenocortical cells, MVDP is responsible for detoxifying isocaproaldehyde generated by steroidogenesis.