Effects of inhibitors of CYP1A and CYP2B on styrene metabolism in mouse liver and lung microsomes.
Much of the toxicity of styrene is associated with its bioactivation to styrene oxide. Both liver and lung have been shown to carry out this metabolic step, but there are differences reported as to which isomers of cytochrome P450 are responsible for this biotransformation in various species and tissues. CYP2E1, CYP2F, CYP2B, CYP1A1/2 and CYP2C11 have all been implicated. In the current study, alpha-naphthoflavone (alphaNF) and alpha-methylbenzylaminobenzotriazole (MBA), selective inhibitors of CYP1A and CYP2B, were used to ascertain the contributions of these isomers to styrene metabolism in mouse hepatic and pulmonary microsomes. AlphaNF did not inhibit styrene metabolism with microsomal preparations from either tissue. This indicates that CYP1A is unimportant in the metabolism of styrene to styrene oxide. MBA at a very low concentration of 1 microM inhibited the hepatic metabolism of benzyloxyresorufin (a CYP2B substrate) by 87% but caused only a 16 to 19% inhibition of R- and S-styrene oxide formation. This demonstrates that CYP2B plays a minor role in styrene metabolism. At 10 microM, MBA caused an even greater inhibition of styrene metabolism but at that level it also inhibited p-nitrophenol hydroxylation, a CYP2E1-dependent reaction, suggesting a loss of selectivity for this inhibitor at higher concentrations.
Carlson
G P
GP
School of Health Sciences, Purdue University, West Lafayette, IN 47907-1338, USA.
Hynes
D E
DE
Mantick
N A
NA
D000818:Animals; D001571:Benzoflavones / Q000494:pharmacology*; D002701:Chloramphenicol / Q000031:analogs & derivatives / Q000494:pharmacology; D019363:Cytochrome P-450 CYP1A1 / Q000037:antagonists & inhibitors*; D019362:Cytochrome P-450 CYP2B1 / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008168:Lung / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D010078:Oxazines / Q000378:metabolism; D020058:Styrene / Q000378:metabolism*; D014230:Triazoles / Q000494:pharmacology*
D001571:Benzoflavones; D004791:Enzyme Inhibitors; D010078:Oxazines; D014230:Triazoles; C059849:alpha-methylbenzylaminobenzotriazole; C087184:2-chloro-2-fluoro-N-(2-(4-nitrophenyl)ethyl)acetamide; D020058:Styrene; C007649:ethoxyresorufin; C011512:alpha-naphthoflavone; D002701:Chloramphenicol; D019363:Cytochrome P-450 CYP1A1; D019362:Cytochrome P-450 CYP2B1