TY - JOUR

T1 - Enantioselective mixture toxicity of the azole fungicide imazalil with the insecticide Α-cypermethrin in Chironomus riparius

T2 - Investigating the importance of toxicokinetics and enzyme interactions

AU - Kuhlmann, Janna

AU - Kretschmann, Andreas C.

AU - Bester, Kai

AU - Bollmann, Ulla E.

AU - Dalhoff, Kristoffer

AU - Cedergreen, Nina

PY - 2019/6/1

Y1 - 2019/6/1

N2 - The fungicide imazalil is a chiral compound with one R- and one S-enantiomer. Enantiomers, while having the same chemical properties, can differ in their biological activity expressed as efficacy/toxicity as well as in their degradation kinetics and pathways. Azoles such as imazalil have been shown to synergize the effect of pyrethroid insecticides like α-cypermethrin through inhibition of cytochrome P450 monooxygenase responsible for pyrethroid detoxification. The aim of this study was to investigate, if the enantiomers of imazalil are selective in their synergistic potential in a mixture with a pyrethroid insecticide tested in Chironomus riparius. Potential enantioselectivity was studied on the level of uptake and elimination, inhibition of cytochrome P450 activity measured in vitro and in vivo and on synergistic potential of α-cypermethrin induced immobilization. Synergy was measured as an increase in α-cypermethrin toxicity after 144h applying a constant non-lethal imazalil concentration of 0.65 μmol/L. The R- and S-imazalil enantiomers increased α-cypermethrin toxicity from an EC50 of 1580 ± 980 pmol/L to an EC50 of 83 ± 10 pmol/L and 53 ± 8 pmol/L, respectively. The relatively small potency difference between imazalil enantiomers could not be explained by the in vitro cytochrome P450 inhibition, as the IC50 values were similar (0.11 ± 0.01 and 0.09 ± 0.01 μmol/L for R- and S-imazalil). Measuring in vivo P450 inhibition and the toxicokinetic of imazalil did not show a clear trend of selectivity towards one or the other enantiomer. The study therefore suggests that cytochrome P450 enzymes involved in detoxification in C. riparius are not enantioselective for imazalil.

AB - The fungicide imazalil is a chiral compound with one R- and one S-enantiomer. Enantiomers, while having the same chemical properties, can differ in their biological activity expressed as efficacy/toxicity as well as in their degradation kinetics and pathways. Azoles such as imazalil have been shown to synergize the effect of pyrethroid insecticides like α-cypermethrin through inhibition of cytochrome P450 monooxygenase responsible for pyrethroid detoxification. The aim of this study was to investigate, if the enantiomers of imazalil are selective in their synergistic potential in a mixture with a pyrethroid insecticide tested in Chironomus riparius. Potential enantioselectivity was studied on the level of uptake and elimination, inhibition of cytochrome P450 activity measured in vitro and in vivo and on synergistic potential of α-cypermethrin induced immobilization. Synergy was measured as an increase in α-cypermethrin toxicity after 144h applying a constant non-lethal imazalil concentration of 0.65 μmol/L. The R- and S-imazalil enantiomers increased α-cypermethrin toxicity from an EC50 of 1580 ± 980 pmol/L to an EC50 of 83 ± 10 pmol/L and 53 ± 8 pmol/L, respectively. The relatively small potency difference between imazalil enantiomers could not be explained by the in vitro cytochrome P450 inhibition, as the IC50 values were similar (0.11 ± 0.01 and 0.09 ± 0.01 μmol/L for R- and S-imazalil). Measuring in vivo P450 inhibition and the toxicokinetic of imazalil did not show a clear trend of selectivity towards one or the other enantiomer. The study therefore suggests that cytochrome P450 enzymes involved in detoxification in C. riparius are not enantioselective for imazalil.

KW - Chiral

KW - Enantiomers

KW - Mixture toxicity

KW - Pesticides

KW - Synergy

UR - http://www.scopus.com/inward/record.url?scp=85063112275&partnerID=8YFLogxK

U2 - 10.1016/j.chemosphere.2019.03.023

DO - 10.1016/j.chemosphere.2019.03.023

M3 - Journal article

C2 - 30875499

AN - SCOPUS:85063112275

VL - 225

SP - 166

EP - 173

JO - Chemosphere

JF - Chemosphere

SN - 0045-6535

ER -