Rifampicin-induced CYP3A4 activation in CTX patients cannot replace chenodeoxycholic acid treatment

Auryan Szalat, Pavel Gershkovich, Alon Ben-Ari, Aviv Shaish, Yael Liberman, Eti Boutboul, Marc Gotkine, Amnon Hoffman, Dror Harats, Eran Leitersdorf, Vardiella Meiner

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Cerebrotendinous xanthomatosis (CTX) is a rare neurodegenerative disorder with cholestanol accumulation resulting from mutations in the sterol 27-hydroxylase gene (CYP27A). Conventional treatment includes chenodeoxycholic acid and HMG-CoA reductase inhibitors. Mice with disrupted Cyp27A (Cyp27 KO) do not show elevated cholestanol levels nor develop CTX manifestations. This phenomenon was proposed to be due to murine CYP3A overexpression leading to an alternative pathway for degradation of bile alcohols including cholestanol. Our objective was to examine the influence of CYP3A4 induction on cholestanol elimination in CTX patients. Rifampicin (600 mg/day × 7 days), known to induce the PXR, and thereby to increase CYP3A activity, was used. The degree of CYP3A4 induction was assessed by comparing midazolam pharmacokinetics before and after rifampicin treatment. Cholestanol levels and cholestanol/cholesterol ratios were assayed during the experimental period and compared to a 3 weeks period without treatment. The results show that despite 60% increase in CYP3A4 activity following rifampicin treatment, there is no significant change in cholestanol levels. We conclude that up-regulated expression of CYP3A affects cholestanol elimination in mice differently as compared to its effect in CTX patients. Therefore, CYP3A4 inducers cannot replace chenodeoxycholic acid for the treatment of CTX.

Original languageEnglish (US)
Pages (from-to)839-844
Number of pages6
JournalBiochimica et Biophysica Acta - Molecular and Cell Biology of Lipids
Volume1771
Issue number7
DOIs
StatePublished - Jul 1 2007
Externally publishedYes

Fingerprint

Cerebrotendinous Xanthomatosis
Cholestanol
Chenodeoxycholic Acid
Cytochrome P-450 CYP3A
Rifampin
Therapeutics
Cholestanols
Cholestanetriol 26-Monooxygenase
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Midazolam
Neurodegenerative Diseases
Pharmacokinetics
Cholesterol

Keywords

  • Cerebrotendinous Xanthomatosis
  • Cholestanol
  • CYP3A4
  • Rifampicin

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Biophysics

Cite this

Rifampicin-induced CYP3A4 activation in CTX patients cannot replace chenodeoxycholic acid treatment. / Szalat, Auryan; Gershkovich, Pavel; Ben-Ari, Alon; Shaish, Aviv; Liberman, Yael; Boutboul, Eti; Gotkine, Marc; Hoffman, Amnon; Harats, Dror; Leitersdorf, Eran; Meiner, Vardiella.

In: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids, Vol. 1771, No. 7, 01.07.2007, p. 839-844.

Research output: Contribution to journalArticle

Szalat, A, Gershkovich, P, Ben-Ari, A, Shaish, A, Liberman, Y, Boutboul, E, Gotkine, M, Hoffman, A, Harats, D, Leitersdorf, E & Meiner, V 2007, 'Rifampicin-induced CYP3A4 activation in CTX patients cannot replace chenodeoxycholic acid treatment', Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids, vol. 1771, no. 7, pp. 839-844. https://doi.org/10.1016/j.bbalip.2007.04.012
Szalat, Auryan ; Gershkovich, Pavel ; Ben-Ari, Alon ; Shaish, Aviv ; Liberman, Yael ; Boutboul, Eti ; Gotkine, Marc ; Hoffman, Amnon ; Harats, Dror ; Leitersdorf, Eran ; Meiner, Vardiella. / Rifampicin-induced CYP3A4 activation in CTX patients cannot replace chenodeoxycholic acid treatment. In: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids. 2007 ; Vol. 1771, No. 7. pp. 839-844.
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abstract = "Cerebrotendinous xanthomatosis (CTX) is a rare neurodegenerative disorder with cholestanol accumulation resulting from mutations in the sterol 27-hydroxylase gene (CYP27A). Conventional treatment includes chenodeoxycholic acid and HMG-CoA reductase inhibitors. Mice with disrupted Cyp27A (Cyp27 KO) do not show elevated cholestanol levels nor develop CTX manifestations. This phenomenon was proposed to be due to murine CYP3A overexpression leading to an alternative pathway for degradation of bile alcohols including cholestanol. Our objective was to examine the influence of CYP3A4 induction on cholestanol elimination in CTX patients. Rifampicin (600 mg/day × 7 days), known to induce the PXR, and thereby to increase CYP3A activity, was used. The degree of CYP3A4 induction was assessed by comparing midazolam pharmacokinetics before and after rifampicin treatment. Cholestanol levels and cholestanol/cholesterol ratios were assayed during the experimental period and compared to a 3 weeks period without treatment. The results show that despite 60{\%} increase in CYP3A4 activity following rifampicin treatment, there is no significant change in cholestanol levels. We conclude that up-regulated expression of CYP3A affects cholestanol elimination in mice differently as compared to its effect in CTX patients. Therefore, CYP3A4 inducers cannot replace chenodeoxycholic acid for the treatment of CTX.",
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AU - Shaish, Aviv

AU - Liberman, Yael

AU - Boutboul, Eti

AU - Gotkine, Marc

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