Reduction of benzene metabolism and toxicity in mice that lack CYP2E1 expression.
Transgenic CYP2E1 knockout mice (cyp2e1-/-) were used to investigate the involvement of CYP2E1 in the in vivo metabolism of benzene and in the development of benzene-induced toxicity. After benzene exposure, absence of CYP2E1 protein was confirmed by Western blot analysis of mouse liver samples. For the metabolism studies, male cyp2e1-/- and wild-type control mice were exposed to 200 ppm benzene, along with a radiolabeled tracer dose of [14C]benzene (1.0 Ci/mol) by nose-only inhalation for 6 hr. Total urinary radioactivity and all radiolabeled individual metabolites were reduced in urine of cyp2e1-/- mice compared to wild-type controls during the 48-hr period after benzene exposure. In addition, a significantly greater percentage of total urinary radioactivity could be accounted for as phenylsulfate conjugates in cyp2e1-/- mice compared to wild-type mice, indicating the importance of CYP2E1 in oxidation of phenol following benzene exposure in normal mice. For the toxicity studies, male cyp2e1-/-, wild-type, and B6C3F1 mice were exposed by whole-body inhalation to 0 ppm (control) or 200 ppm benzene, 6 hr/day for 5 days. On Day 5, blood, bone marrow, thymus, and spleen were removed for evaluation of micronuclei frequencies and tissue cellularities. No benzene-induced cytotoxicity or genotoxicity was observed in cyp2e1-/- mice. In contrast, benzene exposure resulted in severe genotoxicity and cytotoxicity in both wild-type and B6C3F1 mice. These studies conclusively demonstrate that CYP2E1 is the major determinant of in vivo benzene metabolism and benzene-induced myelotoxicity in mice.
Valentine
J L
JL
Chemical Industry Institute of Toxicology, Research Triangle Park, North Carolina 27709, USA.
Lee
S S
SS
Seaton
M J
MJ
Asgharian
B
B
Farris
G
G
Corton
J C
JC
Gonzalez
F J
FJ
Medinsky
M A
MA
D000818:Animals; D001273:Atmosphere Exposure Chambers; D001554:Benzene / Q000378:metabolism* / Q000633:toxicity*; D015153:Blotting, Western; D002273:Carcinogens / Q000378:metabolism* / Q000633:toxicity*; D019392:Cytochrome P-450 CYP2E1 / Q000172:deficiency* / Q000502:physiology; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D013045:Species Specificity
D002273:Carcinogens; D019392:Cytochrome P-450 CYP2E1; D001554:Benzene