CYP3A and lipids in health and disease : in females and males

Sex and gender differences in the pharmacokinetics-and dynamics of drugs, have been known for centuries. Women have been regarded as different - a 70 kg male has been the norm in medicine. In the context of clinical studies, fertile women and elderly are referred to as special populations, while palliative patients are referred to as a vulnerable population.

The purpose of the studies in this thesis, was to contribute to an increased knowledge of these populations, with focus on women’s health. Accordingly, we set out to investigate lipid lowering treatment with statins in fertile women and palliative cancer patients. In addition, the menstrual cycle variability in novel lipid biomarkers, in the activity in Cytochrome p-450 3A enzyme (CYP3A) and in microbiota TMAO was explored.

In study І, we investigated the effect of treatment with lipid-lowering statins on drug metabolizing CYPs and transporters in hepatic tissue. Patients with gallstones planned for elective cholecystectomy, were subjected to four weeks of statins or placebo treatment. Atorvastatin treatment resulted in an induction of the mRNA expression in uptake and efflux transporters in hepatocytes. In addition, the previously shown higher expression of mRNA of hepatic CYP3A enzyme in fertile women, was confirmed. Next, sex differences in the discontinuation of lipid lowering treatment with statins in palliative cancer patients, were examined in study ІІ. While females had their statin treatment terminated on average 10 months prior to death, males had their treatment ended on average 4 months prior to death. 79 % of the females treated with statin did not have cardiovascular disease, as opposed to 52% of males.

In study ІІІ & ІV, the menstrual cycle variability in novel lipid biomarkers for CVD, non HDL-C, ApoB and remnant-C and the endogenous marker of CYP3A activity 6β hydroxycortisol/cortisol (6β-OHC/C) in urine were evaluated in the same cohort. In addition, the menstrual variability of and associations between, gut microbiota metabolite TMAO in blood and the biomarkers, were determined. In study ІІІ, ApoB and HDL ratio of non-HDL-cholesterol were higher during the follicular phase. Triglyceride rich lipoprotein remnant-cholesterol, was higher during the luteal phase, compared to the ovulatory phase. Sampling of pro atherogenic ApoB and non-HDL-C could ideally be performed in the follicular phase. For patients with Metabolic Syndrome and dyslipidemia, sampling during the luteal phase, may be considered. There was no menstrual cycle variability in TMAO. A significant association between 6β-OHC/C and microbiota TMAO, was shown for the ovulatory and luteal phase in study ІV. In addition, there was a relationship between 6β OHC/C and sex hormone progesterone. Finally, there was no menstrual cycle variability in 6β-OHC/C.

Finally, in study V, we assessed CYP3A activity measured as 4β hydroxycholesterol/cholesterol (4β-OHC/C) in blood, in End-of-Life palliative cancer patients. The median 4β-OHC/C was higher in female and male patients, than in the young and elderly controls, suggesting that CYP3A activity is maintained until the end of life.

List of scientific papers

I. Atorvastatin treatment induces uptake and efflux transporters in the liver. Björkhem-Bergman, L., Bergström, H., Johansson, M., Parini P., Eriksson, M., Rane, A., Ekström, L. Drug Metab Dispos. 2013;41(9):1610-15.
https://doi.org/10.1124/dmd.113.051698

II. Differences in discontinuation of statin treatment in women and men with advanced cancer disease. Bergström, H,Brånvall, E, Helde-Frankling, M, Björkhem-Bergman, L. Biol Sex Differ. 2018;9(1):47.
https://doi.org/10.1186/s13293-018-0207-5

III. Variations in biomarkers of dyslipidemia and dysbiosis during the menstrual cycle: a pilot study in healthy volunteers. Bergström, H., Ekström, L., Warnqvist, A., Bergman, P., Björkhem-Bergman, L. BMC Women’s Health. 2021;21(1):166.
https://doi.org/10.1186/s12905-021-01306-4

IV. CYP3A activity during the menstrual cycle measured by the endogenous biomarker 6β-hydroxycortisol/cortisol ratio. Bergström, H., Lindahl, A., Warnqvist, A., Diczfalusy, U., Ekström, L., Björkhem-Bergman, L. Pharmacological Research & Perspectives. 2021; 9(6):e00884.
https://doi.org/10.1002/prp2.884

V. CYP3A activity in end-of-life patients measured by 4β hydroxycholesterol/cholesterol ratio, in men and women. Bergström, H., Helde-Frankling, M., Klasson, C., Lövgren-Sandholm, A., Diczfalusy, U., Björkhem-Bergman, L. Cancers. 2021, 13(18), 4689.
https://doi.org/10.3390/cancers13184689