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Chronic Suppression of Cholesterol 7-Hydroxylase by Dietary Chenodeoxycholic Acid in Neonatal Guinea Pigs: Its Effect on Subsequent Bile Acid Metabolism in the Adult^1,2,

Aslam S. Hassan^3,*, Remy L. Yunker, D. Jean Sprinkle^* and M. T. Ravi Subbiah^4,*,,

^* Departments of Pathology Medicine, University of Cincinnati Medical Center, Cincinnati, OH 45267

Treatment of neonatal guinea pigs with cholestyramine persistently increases the activity of hepatic cholesterol 7-hydroxylase (CH-7), the rate-limiting enzyme of bile acid biosynthesis. In this study, we examined whether CH-7 activity could be persistently inhibited by manipulations (chenodeoxycholic acid feeding) during neonatal life. Male Hartley guinea pigs (2–3 days old) were fed 0.25% chenodeoxycholic acid (CDCA)-supplemented diet for 10 days or 6 weeks. Feeding CDCA for 10 days increased plasma cholesterol [controls (C), 25 ± 3 vs. CDCA, 34 ± 2 mg/dl]. Bile acid pool in animals fed CDCA for 10 days was nearly fivefold greater than controls (C, 5.8 ± 0.3 vs. CDCA, 29.1 ± 0.9 mg/100 g body weight), whereas CH-7 activity was almost completely inhibited [C, 1.83 ± 0.4 vs. CDCA, 0.02 ± 0.02 pmol/(mg·minute)]. Four weeks after stopping CDCA feeding, CH-7 was greater in the CDCA-fed animals (C, 0.47 ± 0.03 vs. CDCA, 0.67 ± 0.05). This was associated with a greater bile acid pool in these animals (C, 3.0 ± 0.2 vs. CDCA, 5.8 ± 0.4). We conclude that CDCA fed to neonatal guinea pigs inhibits CH-7 activity. This inhibition is not permanent, however, since CH-7 activity increases following withdrawal from chronic CDCA feeding.

KEY WORDS: • bile acid pool • enterohepatic circulation • fecal sterols • hepatic ultrastructure • cholestasis • lithocholic acid

¹ This is paper no. 13 in the series Sterol and Bile Acid Metabolism During Development. Reference 36 is paper no. 12 in this series.

² Supported in part by grant HL 24263 from the National Heart, Lung and Blood Institute.

³ Present address: Department of Veterinary Biosciences, University of Illinois, 2001 S. Lincoln, Urbana, IL 61801.

⁴ To whom reprint requests should be sent.

Manuscript received 13 September 1982.