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

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.

Modelling changes in the pharmacokinetics of tacrolimus during pregnancy after kidney transplantation: A retrospective cohort study

“…This might be explained by the fact that we took the genotype into account and not the protein activity, of which the latter can be influenced by oestrogen activity. The effect of oestrogen on CYP3A protein activity during pregnancy is potentially greater than the effect of genetics on CYP3A protein activity, resulting in the nullification of the genotype effect 46–48 . Another explanation might be the absence of CYP3A5*1 homozygotes (CYP3A5 expressers) in this small, mostly Caucasian population.…”

“…The effect of oestrogen on CYP3A protein activity during pregnancy is potentially greater than the effect of genetics on CYP3A protein activity, resulting in the nullification of the genotype effect. [46][47][48] Another explanation might be the absence of CYP3A5*1 homozygotes (CYP3A5 expressers) in this small, mostly Caucasian population. We observed a decrease in median serum creatinine and increase in median eGFR in our population (Table 1), which is consistent with previous findings.…”

Pregnancy related hormones increase CYP3A mediated buprenorphine metabolism in human hepatocytes: a comparison to CYP3A substrates nifedipine and midazolam

“…The impact of CYP3A5 genotype and expresser status on pregnancy-associated changes in CYP3A metabolism requires further study. A recent study in Tanzanian pregnant women showed that the plasma 4β-OH-cholesterol/cholesterol ratio did not significantly differ in CYP3A5 expressers and non-expressers ( Mlugu et al, 2022 ). Similar to nor-BUP, this may be explained by a minor contribution of CYP3A5 to 4β-OH-cholesterol formation in vitro ( Bodin et al, 2002 ).…”

“…Probe substrate studies in pregnant volunteers have shown that CYP3A metabolic activity, measured by 1-OH-MDZ formation clearance, urinary excretion of dextromethorphan/3-OH-dextromethorphan ratio, or plasma 4β-OH-cholesterol/cholesterol ratio, is increased by approximately 1.5–2.0-fold during pregnancy ( Tracy et al, 2005 ; Hebert et al, 2008 ; Kim et al, 2018 ; Mlugu et al, 2022 ). Because it is well-established that hepatic CYP3A protein concentration and metabolite formation are directly related ( Kronbach et al, 1989 ; Wolbold et al, 2003 ), the central hypothesis has been that the gestational surge in PRHs induces CYP3A4 transcriptional regulation via nuclear receptor activation, and subsequent increases in CYP3A4 protein expression in hepatocytes drive increases in CYP3A4 metabolism ( Jeong, 2010 ).…”

Malaria Treatment Landscape: Current Trends and Future Directions

“…Sub-optimal antimalarial plasma exposure resulting in treatment failure is another challenge facing the effective treatment of malaria. Sub-optimal drug concentrations occur in pregnant women possibly due to pregnancy-related increased CYP enzyme activity [68]. Children also have higher clearance of antimalarial drugs leading to subtherapeutic concentrations [69,70].…”