TY - JOUR

T1 - Oral anti-diabetic drugs as endocrine disruptors in vitro - No evidence for additive effects in binary mixtures

AU - Munkboel, Cecilie Hurup

AU - Hansen, Helene Stenbaek

AU - Jessen, Julie Buchholt

AU - Johannsen, Malene Louise

AU - Styrishave, Bjarne

PY - 2021

Y1 - 2021

N2 - Diabetes is one of the World's most concerning health problems and millions of patients are using anti-diabetic drugs (ADDs) in order to control blood glucose. The in vitro H295R steroidogenesis assay was implemented to investigate endocrine effects of three ADDs, metformin (MET), glimepiride (GLIM), sitagliptin (SIT) and the cholesterol-lowering drug simvastatin (SIM) individually and in three binary mixtures. Steroid hormones were analyzed using LC-MS/MS. Mixture effects were assessed by applying the Concentration Addition (CA) model. All tested drugs and binary mixtures interrupted the H295R steroidogenesis with different potency. The effects of MET:GLIM on the steroidogenesis were overall similar to the steroidogenic profile of GLIM, however effects were less pronounced. The binary mixture of MET:SIT showed overall minor effects on steroid production and only at very high concentrations. The SIM:SIT mixture showed inhibition downstream from cholesterol, which was attributed to the effects of SIM. The CA model partly predicted the effect of MET:SIT on some steroids but significantly overestimated the effects of MET:GLIM and SIM:SIT. Thus, the applicability of the CA model was limited and cocktail effects appeared to be intermediate responses of individual drugs, rather than additive. The complexity of dynamic pathways such as steroidogenesis appears to significantly reduce the use of the CA model. In conclusion, more dynamic models are needed to predict mixture effects in complex systems.

AB - Diabetes is one of the World's most concerning health problems and millions of patients are using anti-diabetic drugs (ADDs) in order to control blood glucose. The in vitro H295R steroidogenesis assay was implemented to investigate endocrine effects of three ADDs, metformin (MET), glimepiride (GLIM), sitagliptin (SIT) and the cholesterol-lowering drug simvastatin (SIM) individually and in three binary mixtures. Steroid hormones were analyzed using LC-MS/MS. Mixture effects were assessed by applying the Concentration Addition (CA) model. All tested drugs and binary mixtures interrupted the H295R steroidogenesis with different potency. The effects of MET:GLIM on the steroidogenesis were overall similar to the steroidogenic profile of GLIM, however effects were less pronounced. The binary mixture of MET:SIT showed overall minor effects on steroid production and only at very high concentrations. The SIM:SIT mixture showed inhibition downstream from cholesterol, which was attributed to the effects of SIM. The CA model partly predicted the effect of MET:SIT on some steroids but significantly overestimated the effects of MET:GLIM and SIM:SIT. Thus, the applicability of the CA model was limited and cocktail effects appeared to be intermediate responses of individual drugs, rather than additive. The complexity of dynamic pathways such as steroidogenesis appears to significantly reduce the use of the CA model. In conclusion, more dynamic models are needed to predict mixture effects in complex systems.

KW - Anti-diabetics

KW - Cocktail effects

KW - Concentration addition model

KW - Endocrine disruption

KW - Polytherapy

KW - Steroidogenesis

KW - DIPEPTIDYL PEPTIDASE-4 INHIBITOR

KW - STEROID-HORMONES

KW - H295R CELLS

KW - SITAGLIPTIN

KW - METFORMIN

KW - PHARMACOKINETICS

KW - WOMEN

KW - STEROIDOGENESIS

KW - SIMVASTATIN

KW - PREDICTION

U2 - 10.1016/j.tiv.2020.105007

DO - 10.1016/j.tiv.2020.105007

M3 - Journal article

C2 - 33002602

VL - 70

JO - Toxicology in Vitro

JF - Toxicology in Vitro

SN - 0887-2333

M1 - 105007

ER -