The production and modification of cytochrome P-450 difference spectra by in vivo administration of methylenedioxyphenyl compounds

Abstract

The in vivo administration of piperonyl butoxide (PB) or propyl isome (PI), both methylenedioxyphenyl compounds, to mice affects the levels of several hepatic cytochrome P-450 spectral interactions. The difference spectrum produced by carbon monoxide (commonly employed as a measurement of cytochrome P-450 levels) is initially lowered in magnitude by both compounds. The reduction is followed by an increase with time indicative of cytochrome induction. This biphasic effect, when produced by piperonyl butoxide, is accompanied by specific changes in the levels of the cytochrome P-450 difference spectra produced by hexobarbital, a type-I substrate, and pyridine, a type-II substrate. In addition, the ethyl isocyanide (EtNC) equilibrium point, calculated from the pH effect on the 455-nm and 430-nm peaks of the ethyl isocyanide-cytochrome P-450 difference spectrum, undergoes a biphasic shift. In contrast, propyl isome has the same effect on the substrate difference spectra as it does on the cytochrome level and produces no change in the ethyl isocyanide equilibrium point with time. Piperonyl butoxide, administered in vivo, produces a cytochrome P-450 difference spectrum when dithionite-reduced microsomes from treated animals are compared at different pH values. This spectrum, when observed by comparing microsomes from treated and untreated animals, has two pH-dependent Soret peaks and is essentially identical to the NADPH-dependent piperonyl butoxide-cytochrome P-450 spectrum produced by in vitro treatment. This spectrum is also produced in vitro by propyl isome and sulfoxide.