A teratogenic compound cis-1-[-4-(p-menthane-8-yloxy)phenyl]piperadine (YM9429) selectively induces skeletal malformations characterized by cleft palate in rat fetuses. In the present study, we investigated the effect of YM9429 on hepatic cytochrome P-450s and their activities in rats. Oral administrations of YM9429 at a dose of 250, 500 or 750 mg/kg daily for 3 days induced cytochrome P-450 contents in a dose-dependent manner. Concomitant induction of enzyme activities of benzphetamine N-demethylase, erythromycin N-demethylase and, to a lesser extent, aminopyrine N-demethylase was observed. Immunoblot analysis revealed that YM9429 up-regulated hepatic levels of CYP2B1/2 and CYP3A1/2 proteins. A single dose of YM9429 at 250 mg/kg induced CYP2B1/2 protein levels significantly. These results suggest that YM9429 is a strong inducer of cytochrome P-450 with characteristics resembling those of phenobarbital.

01 Sep 1996·SteroidsQ4 · MEDICINE

Effect of YM 9429, a potent teratogen, on cholesterol biosynthesis in cultured cells and rat liver microsomes

Q4 · MEDICINE

Article

Author: Akira Honda ; Gerald Salen ; Megumi Honda ; Sarah Shefer ; Ashok K. Batta ; G.Stephen Tint

YM 9429 (cis-1-[4-(p-menthan-8-yloxy)phenyl]piperidine) is a hypolipidemic agent with a potent and specific teratogenicity, inducing cleft palate and skeletal variations in rats. Since cleft palate is generally observed in the Smith-Lemli-Opitz syndrome, a common syndrome of multiple congenital anomalies caused by reduced activity of 7-dehydrocholesterol delta 7-reductase (3 beta-hydroxysteroid delta 7-reductase), the final enzyme in the cholesterol biosynthetic pathway, YM 9429 was suspected of being an inhibitor of this enzyme. To prove this hypothesis, YM 9429 was added to cultured human skin fibroblasts and to cultured Morris hepatoma cells and incubated with [5-3H]mevalonolactone. After 24 h, radiolabeled 7-dehydrocholesterol accumulated in the cells, whereas the formation of radiolabeled cholesterol was markedly reduced. The results indicate that YM 9429 inhibits the conversion of 7-dehydrocholesterol to cholesterol catalyzed by the microsomal enzyme 7-dehydrocholesterol delta 7-reductase. In rat liver microsomes, the mode of inhibition was found to be noncompetitive, with a Ki of 40 microM. These results suggest that YM 9429 induced developmental abnormalities in rats by the same mechanism as the Smith-Lemli-Opitz syndrome. This compound might be useful for studying the pathogenesis of anomalies in animal models of the Smith-Lemli-Opitz syndrome.

01 Aug 1996·Biochemical and Biophysical Research CommunicationsQ3 · BIOLOGY

Inhibition of Insulin-Induced Chondrogenic Differentiation of Embryonic Carcinoma Cells by a Teratogenic Compound YM9429

Q3 · BIOLOGY

Article

Author: Emi Fujino ; Yukio Kuroiwa ; Satoshi Numazawa ; Masakatsu Shibata ; Yoichi Sato ; Takemi Yoshida

A teratogenic compound cis-1-[4-(p-menthane 8-yloxy)phenyl]piperidine (YM9429) induces cleft palate selectively in rat fetuses. The effect of YM9429 on chondrogenic differentiation was investigated using mouse embryonic carcinoma ATDC5 cells that produce chondrocyte specific extracellular matrix upon insulin stimulation. YM9429 at concentrations that showed no growth-inhibitory effect on logarithmic proliferating cells suppressed insulin-mediated increases in Alcian blue staining and expression of type II collagen almost completely. Under the identical conditions, insulin-stimulated cell growth was only partially blocked by the compound. The early response genes such as c-fos and c-jun were induced by insulin even in the presence of YM9429. On the other hand, YM9429 inhibited accumulation of cAMP during the differentiation process. These results indicate that YM9429 selectively inhibits in vitro chondrogenic differentiation of ATDC5 cells.

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