Mixture effects between different azoles and β-naphthoflavone on the CYP1A biomarker in a fish cell line

New Conceptual Toxicokinetic Model to Assess Synergistic Mixture Effects between the Aromatic Hydrocarbon β-Naphthoflavone and the Azole Nocodazole on the CYP1A Biomarker in a Fish Cell Line

“…The parameters in the model are fitted to experimental EROD data from a previous study where the cells were exposed to different mixtures of BNF and NOC in a time course study (Table S1). , …”

“…Hence, we model the EROD activity that can be compared with the data. , Equation is the rate of change in the EROD activity of free CYP1A enzymes ( E f EROD ) over time. Note that the two functions f ( X ) and g ( Y ) have not been changed and are given by eqs and .…”

“…, clotrimazole, ketoconazole, nocodazole (NOC), omeprazole, prochloraz, and propiconazole] have been shown to interact with the CYP system in fish and fish cells. − Most azoles act as potent inhibitors of CYP1A enzyme activities but weak inducers of CYP1A transcription in fish. − Previous studies on the Poeciliopsis lucida hepatocellular carcinoma (PLHC-1) cell line show that the benzimidazole and microtubule disassembling drug NOC alone acted as a potent inhibitor of the CYP1A enzyme activity and a weak inducer of CYP1A expression. Compared to β-naphthoflavone (BNF), NOC is 1 order of magnitude less potent and about 50 times less efficient to induce CYP1A expression. , However, a synergistic mixture effect with NOC and the prototypical AhR agonist, BNF, was seen as increased induction of CYP1A . Although BNF and NOC have different MoA, they seem to share a common elimination pathway.…”

“…Although BNF and NOC have different MoA, they seem to share a common elimination pathway. Thus, PLHC-1 cells exposed to NOC were more sensitive to BNF exposures compared to cells exposed to BNF alone . The synergistic mixture effect is based on the hypothesis that NOC occupies the CYP1A enzymes, inhibiting the CYP1A-dependent metabolism of BNF, which in turn enhances the BNF-mediated AhR-CYP1A signaling (Figure ).…”

“…The aim of this study was to create a new conceptual toxicokinetic model to describe the toxicokinetic interaction between BNF and NOC, where the dominant effect of NOC is direct inhibition of CYP1A enzymes and the dominant effect of BNF is induction of CYP1A transcription via activation of AhR. This is a first attempt to create a mathematical bottom-up model for synergistic mixture effects where we fit a multidimensional function to a given experimental data set from a previous study using an auxiliary nonadditive model. , The time dynamics is a key factor in the toxicokinetic interactions. We hypothesized that by constructing a model using ordinary differential equations (ODEs), we can describe how the concentrations of the chemicals change over time and their resulting effect on the CYP1A biomarker.…”