Impact of dietary fat and obesity on biotransformation, tissue distribution and bioactivity of isoflavones
Final Report Abstract
The aim of the project was to investigate the impact of dietary fat and of obesity on biotransformation, tissue distribution and bioactivity of the soy isoflavones (IF) daidzein (DAI) and genistein (GEN) as well as to characterize species-specific differences in the biotransformation of IF to allow a profound assessment of the transferability of animal studies to the human situation. For all studies conducted in this project as well as in the entire project “IsoCross” a commercially available soy extract was used. The extract was analyzed in detail regarding its IF content and profile and its further composition. To clarify the effect of dietary fat on the ADME of IF, a short-term double-blinded placebo controlled cross-over study was conducted with 11 postmenopausal women (age 61.5 ± 5.0 years, BMI 25.2 ± 1.9 kg/m²) which received either a low fat (21.3% energy from fat) or a high fat diet (35.4% energy from fat) during the IF intervention. Only slight and not significant effects of dietary fat was observed on biokinetic parameters (AUC, Cmax or tmax), but the 24 h-renal excretion was significantly higher in the high fat group, although the effect was overall moderate. DAI-7-sulfo-4’-glucuronide, GEN-7-sulfo- 4’-glucuronide as well as GEN-7,4’-diglucuronide were the main metabolites. By analyzing the various plasma lipoprotein fractions, we could confirm that a substantial part of IF is associated to the LDL fraction (27% in case of DAI and 15% in case of GEN) indicating that LDL might contribute to the uptake of polar IF phase II metabolites into the tissue via LDL-receptor mediated endocytosis. Using cell culture models (transfected HEK cells) four transporters, namely human SOAT, NTCP, OATP2B1, and OAT4, were identified as carriers for IF monoglucuronides and monosulfates from the blood into the target tissues like the mammary gland. In the long-term intervention study 170 postmenopausal women (BMI between 21 and 30 kg/m²) received the soy extract for 3 months (117.4 mg IF per day). No significant differences in receptor expression (either for LDLR, or for CD36) were found between the two groups after the intervention for all investigated cells and their subtypes, respectively. Furthermore, body fat (%) does not exhibit an impact on the receptor expression during IF intervention, except for LDLR expression on B-cells. In conclusion, regular IF consumption over 12 weeks does not influence LDL-receptor expression in PBMC. No IF effects were found for total cholesterol and HDL cholesterol concentrations. Surprisingly, LDL cholesterol concentrations significantly increased in the verum group after the 12 weeks of IF intervention and triglyceride concentrations tended to increase. No significant effects due to the intervention were shown for all anthropometric parameters and blood count, except of leucocytes (%). Thyroid hormones, insulin, leptin and safety parameters were not affected by the IF intervention. No IF intervention effect on visceral adipose tissue has been detected. Equol producer phenotype had no major impact on anthropometric, lipid and LDLR parameters. Investigating the metabolism of IF in different species, we observed marked differences especially in IF phase II metabolism between humans, rats and mice as well as sex distinctions in rats and mice. In women di-conjugated phase II metabolites predominate compared to female rats and mice. In addition, rats and even more mice showed higher portions of IF aglycones in the plasma. These differences were also confirmed for breast tissue received from women and female rats. We conclude that this observation has essential impact on the interpretation of results from animal studies and has to be taken into account when applying such findings to humans.
Publications
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(2013) Proliferative and estrogenic sensitivity of the mammary gland are modulated by isoflavones during distinct periods of adolescence. Archives of Toxicology 87:1129-1140
Molzberger AF, Soukup ST, Kulling SE, Diel P
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(2014) Quantification of soy isoflavones and their conjugative metabolites in plasma and urine: an automated and validated UHPLC-MS/MS method for use in large-scale studies. Analytical and Bioanalytical Chemistry, 406:6007-6020
Soukup ST, Al-Maharik N, Botting N, Kulling SE
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(2014) Transport of the soy isoflavone daidzein and its conjugative metabolites by the carriers SOAT, NTCP, OAT4, and OATP2B1. Archives of Toxicology
Grosser G, Döring B, Ugele B, Geyer J, Kulling SE, Soukup ST
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Isoflavone und ihre Wirkung: Datenlage und aktuelle Forschungsprojekte. Lebensmittelchemie 2014; 68, 62-66
Kulling SE, Lehmann L
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(2015) Dose-dependent effects of isoflavone exposure during early lifetime on the rat mammary gland: Studies on estrogen sensitivity, isoflavone metabolism, and DNA methylation. Molecular Nutrition & Food Research, 59:270-283
Blei T, Soukup ST, Schmalbach K, Pudenz M, Möller FJ, Egert B, Wörtz N, Kurrat A, Müller D, Vollmer G, Gerhäuser C, Lehmann L, Kulling SE, Diel P
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(2015) Lifelong exposure to dietary isoflavones reduces risk of obesity in ovariectomized Wistar rats. Molecular Nutrition & Food Research
Kurrat A, Blei T, Kluxen FM, Mueller DR, Piechotta M, Soukup ST, Kulling SE, Diel P
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Dose-dependent effects of isoflavone exposure during early lifetime on development and androgen sensitivity in male Wistar rats. Molecular Nutrition & Food Research 60,2, February 2016, Pages 325-336
Müller D, Basso F, Kurrat A, Soukup ST, Niehoff A, Kulling SE, Diel P
