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theses

Pyrethroids are a class of semi-volatile organic compounds (SVOCs) ubiquitously used as pesticides. These compounds are known to be metabolized by hydrolytic, oxidative, and conjugative means. The oxidative pathway is performed by cytochrome P450 enzymes (CYPs), which exhibit an overlap in having pyrethroids as substrates. This metabolic overlap produces a risk for enzyme inhibition, providing the focus of this study. It was hypothesized that pyrethroids would inhibit CYPs because metabolism of pyrethroids is shared across these critical pathways. Wistar rat liver microsomes (RLMs) were incubated with a spectrophotometric substrate, 7-ethoxyresorufin (7-ER), which is metabolized to resorufin via ethoxyresorufin O-deethylation (EROD), to measure CYP1A activity. In order to investigate potential gender differences in CYP profiles, all treatments were replicated in untreated male and female rat liver microsomes (RLMs). Measurement of EROD in male RLMs produced a Km of 9.83 ± 5.56 µM and a Vmax of 0.44 ± 0.14 nmol/min/mg protein, while female RLMs produced a Km of 7.84 ± 0.79 µM and a Vmax of 0.46 ± 0.02 nmol/min/mg protein. Co-incubation of 7-ER with permethrin or cypermethrin were used to determine inhibition concentrations. Upon addition of permethrin, male RLMs experienced up to 20% reduction in reaction velocity, while the female RLMs experienced up to 30% reduction. Male RLMs produced less than 10% reduction in reaction velocity when treated with cypermethrin, while the female RLMs produced up to 20% reduction. Subsequent incubations used combinations of permethrin and cypermethrin to determine if there was an additive effect. Combinations produced reaction velocities with non-significant reductions when compared to control, all were within 10%, in both the male or female RLMs. Pyrethroids inhibited CYP1A activity as measured by EROD and the female RLMs seem to be more sensitive to this inhibition. Despite co-administration of permethrin and cypermethrin, even at the highest individual inhibition concentrations, the inhibition produced was not additive, disproving the hypothesis.

ETD_9265

M.S.

Includes bibliographical references

by Nicole Renkel

doi:10.7282/t3-xq5r-0z27

ETD graduate

The author owns the copyright to this work.