Normal and inhibited cholesterol synthesis in the cultured rat embryo.
The Smith-Lemli-Opitz syndrome-affected fetus presents a deficiency in delta7-dehydrocholesterol reductase, the last enzymatic step in the cholesterol biosynthesis pathway. Development of the abnormal human fetus takes place in a normal environment as the heterozygous mother's cholesterolemia remains normal. An animal model for this disease has been obtained from the offspring of pregnant rats treated with "distal" inhibitors of delta7-dehydrocholesterol reductase, AY-9944 or BM15766. In the animal model, embryonic development occurs in a disturbed environment characterized by hypocholesterolemia and accumulation of delta7-dehydrocholesterol and delta8-dehydrocholesterol in the maternal serum. The purpose of the present study was to assess, in cultured rat embryos at early developmental stages, the relative contributions of exogenous and de novo synthesized cholesterol in the total embryonic cholesterol, according to the conditions of normal and altered de novo biosynthesis. Cultured rat embryos are able to synthesize cholesterol as shown by 13C-incorporation into cholesterol from 13C-labeled precursors added to the culture medium. De novo cholesterol biosynthesis is altered by addition to the culture medium of AY-9944 which inhibits the delta7-dehydrocholesterol reductase and the delta8-delta7-sterol isomerase as suggested by the emergence of characteristic aberrant sterols in the embryonic tissues. Cholesterol-rich serum used for embryo culture alters the pattern in a way that confirms that the rat embryos are able to import exogenous cholesterol which down-regulates de novo cholesterol biosynthesis. Exogenous cholesterol substitutes for the deficit in a manner efficient enough to prevent the embryonic abnormalities induced by AY-9944.
Llirbat
B
B
Laboratoire de Spectrometrie de masse, URA CNRS 1283, CHU Saint Antoine, Paris, France.
Wolf
C
C
Chevy
F
F
Citadelle
D
D
Bereziat
G
G
Roux
C
C
D000222:Adaptation, Physiological; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D002784:Cholesterol / Q000096:biosynthesis*; D046508:Culture Techniques; D004353:Drug Evaluation, Preclinical; D004622:Embryo, Mammalian / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015394:Molecular Structure; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D044925:Oxidoreductases Acting on CH-CH Group Donors; D051381:Rats; D017208:Rats, Wistar; D012016:Reference Values; D001371:trans-1,4-Bis(2-chlorobenzaminomethyl)cyclohexane Dihydrochloride / Q000494:pharmacology
D000924:Anticholesteremic Agents; D004791:Enzyme Inhibitors; D001371:trans-1,4-Bis(2-chlorobenzaminomethyl)cyclohexane Dihydrochloride; D002784:Cholesterol; D010088:Oxidoreductases; D044925:Oxidoreductases Acting on CH-CH Group Donors; C019995:7-dehydrocholesterol reductase