Influence of the SLCO1B1*1b and *5 haplotypes on pravastatin’s cholesterol lowering capabilities and basal sterol serum levels
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- 作者：Thomas Gerloff ; Melanie Schaefer ; Jessica Mwinyi ; Andreas Johne ; Thomas Sudhop ; Dieter L眉tjohann ; Ivar Roots and Klaus von Bergmann
- 关键词：Bile acids ; HMG CoA reductase inhibition ; Lathosterol ; Nuclear receptor ; Oxysterols ; Pharmacogenetics ; SLCO1B1
- 刊名：Naunyn-Schmiedeberg's Archives of Pharmacology
- 出版时间：April 2006
- 出版年：2006
- 期刊代码：190_0028-1298
- 类别：bio
- 卷：373
- 期：1
- 页码：45-50
- 数据来源：sp
摘要
We previously showed that variant SLCO1B1 haplotype *1b (A388G) accelerates and that *5 (T521C) delays hepatocellular uptake of the HMG-CoA reductase inhibitor pravastatin [Mwinyi et al. (2004): Clin Pharmacol Ther 75:415–421]. In the present study we checked for differential effects of variant SLCO1B1 haplotypes on hepatocellular cholesterol synthesis. We analyzed the serum levels of cholesterol, lathosterol, and campesterol in healthy white males which had been grouped on the basis of their SLCO1B1 haplotype: *1a (n=10), *1b (n=10), and *5 (n=8). The subjects received a single oral dose of 40 mg pravastatin. Cholesterol and lathosterol levels were lower in all subjects following pravastatin intake for up to 24. Median levels 6 h post-dosing of lathosterol decreased in each SLCO1B1 haplotype group in the rank order of *1b (−0.11 mg dl–1; min–max: −0.20 to −0.04; p=0.005) > *1a (−0.09 mg dl–1; min–max: −0.22 to −0.05; p=0.005) > *5 (−0.07 mg dl–1; min–max: −0.17 to −0.05; p=0.012). Lathosterol median-change values were significantly greater in haplotype *1b than in haplotype *5 individuals (p=0.041, non-adjusted), which was congruent with the extent of mean changes in lathosterol-to-cholesterol ratios, although the latter did not reach statistical significance. Post-treatment serum levels of campesterol were not affected by SLCO1B1 haplotype. Interestingly, sterol basal serum levels tended to be highest in *1b carriers, followed by those in *1a and *5 individuals, with significant differences in lathosterol concentrations between the *1b and *5 (p=0.041, non-adjusted) haplotype group. Our findings suggest an association of SLCO1B1*1b and *5 haplotypes to pravastatin’s inhibition of the hepatocellular HMG-CoA reductase. Furthermore, SLCO1B1 haplotypes seem to play a role in basal cholesterol homeostasis.