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. 2022 Dec 2;23(23):15168.
doi: 10.3390/ijms232315168.

Pregnancy Increases CYP3A Enzymes Activity as Measured by the 4β-Hydroxycholesterol/Cholesterol Ratio

Eulambius M Mlugu  1   2 , Omary M Minzi  3 , Appolinary A R Kamuhabwa  3 , Ulf Diczfalusy  4 , Eleni Aklillu  1
Affiliations

Pregnancy Increases CYP3A Enzymes Activity as Measured by the 4β-Hydroxycholesterol/Cholesterol Ratio

Eulambius M Mlugu et al. Int J Mol Sci. .

Abstract

Changes in cortisol and other hormones during pregnancy may alter CYP3A enzymes activity, but data from sub-Saharan Africa are sparse. We investigated the effect of pregnancy and CYP3A5 genotypes on CYP3A enzymes activity using the plasma 4β-hydroxycholesterol (4β-OHC)/cholesterol (Chol) ratio, a known endogenous biomarker. Tanzanian pregnant women (n = 110) and non-pregnant women (n = 59) controls were enrolled. Plasma 4β-OHC and Chol were determined in the second and third trimesters for pregnant women and once for non-pregnant women using gas chromatography−mass spectrometry. Genotyping for CYP3A5 (*3, *6, *7) was performed. Wilcoxon Signed-Rank Test and Mann−Whitney U test were used to compare the median 4β-OHC/Chol ratio between trimesters in pregnant women and between pregnant and non-pregnant women. Repeated-measure ANOVA was used to evaluate the effect of the CYP3A5 genotypes on the 4β-OHC/Chol ratio in pregnant women. No significant effect of the pregnancy status or the CYP3A5 genotype on the cholesterol level was observed. The plasma 4β-OHC/Chol ratio significantly increased by 7.3% from the second trimester to the third trimester (p = 0.02). Pregnant women had a significantly higher mean 4β-OHC/Chol ratio than non-pregnant women, (p < 0.001). In non-pregnant women, the mean 4β-OHC/Chol ratio was significantly lower in carriers of defective CYP3A5 alleles (*3, *6 or *7) as compared to women with the CYP3A5*1/*1 genotypes (p = 0.002). Pregnancy increases CYP3A enzymes activity in a gestational-stage manner. The CYP3A5 genotype predicts CYP3A enzymes activity in the black Tanzanian population, but not during pregnancy-mediated CYP3A enzyme induction.

Keywords: 4β-hydroxycholesterol/cholesterol; CYP3A; pregnancy; trimester.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Figures

Figure 1
Figure 1
Comparison of the geometric mean of the 4β-OHC/Chol × 104 ratio between non-pregnant and pregnant women in the second and third trimesters. The box plots show the mean ± SD, while whiskers denote the minimum and maximum values.
Figure 2
Figure 2
Comparison of the geometric mean of the 4β-OHC/Chol × 104 ratio between CYP3A5 genotypes among pregnant women in the second and third trimesters. The red squares indicate the geometric mean of the 4β-OHC/Chol × 104 ratio in women with CYP3A5*1/*1 genotypes, while the blue dots indicate the geometric mean of the 4β-OHC/Chol × 104 ratio in carriers of defective CYP3A5*3*6*7 alleles in the second and third trimesters. The whiskers indicate the 95% confidence interval of the means.
Figure 3
Figure 3
Comparison of the geometric mean of the 4β-OHC/Chol × 104 ratio between CYP3A5 genotypes among non-pregnant women. The box plot shows the mean ± SD, while the whiskers denote the minimum and maximum values.
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