Genetic susceptibility to benzene-induced toxicity: role of NADPH: quinone oxidoreductase-1.
Enzymes that activate and detoxify benzene are likely genetic determinants of benzene-induced toxicity.NAD(P)H: quinone oxidoreductase-1 (NQO1) detoxifies benzoquinones, proposed toxic metabolites of benzene. NQO1 deficiency in humans is associated with an increased risk of leukemia, specifically acute myelogenous leukemia, and benzene poisoning. We examined the importance of NQO1 in benzene-induced toxicity by hypothesizing that NQO1-deficient (NQO1-/-) mice are more sensitive to benzene than mice with wild-type NQO1 (NQO1+/+; 129/Sv background strain). Male and female NQO1-/- and NQO1+/+ mice were exposed to inhaled benzene (0, 10, 50, or 100 ppm) for 2 weeks, 6 h/day, 5 days/week. Micronucleated peripheral blood cells were counted to assess genotoxicity. Peripheral blood counts and bone marrow histology were used to assess hematotoxicity and myelotoxicity. p21 mRNA levels in bone marrow cells were used as determinants of DNA damage response. Female NQO1-/- mice were more sensitive (6-fold) to benzene-induced genotoxicity than the female NQO1+/+ mice. Female NQO1-/- mice had a 9-fold increase (100 versus 0 ppm) in micronucleated reticulocytes compared with a 3-fold increase in the female NQO1+/+ mice. However, the induced genotoxic response in male mice was similar between the two genotypes (> or = 10-fold increase at 100 ppm versus 0 ppm). Male and female NQO1-/- mice exhibited greater hematotoxicity than NQO1+/+ mice. p21 mRNA levels were induced significantly in male mice (>10-fold) from both strains and female NQO1-/- mice (> 8-fold), which indicates an activated DNA damage response. These results indicate that NQO1 deficiency results in substantially greater benzene-induced toxicity. However, the specific patterns of toxicity differed between the male and female mice.
Bauer
Alison K
AK
CIIT Centers for Health Research, Research Triangle Park, North Carolina 27709, USA. bauer1@niehs.nih.gov
Faiola
Brenda
B
Abernethy
Diane J
DJ
Marchan
Rosemarie
R
Pluta
Linda J
LJ
Wong
Vicki A
VA
Roberts
Kay
K
Jaiswal
Anil K
AK
Gonzalez
Frank J
FJ
Butterworth
Byron E
BE
Borghoff
Susan
S
Parkinson
Horace
H
Everitt
Jeffrey
J
Recio
Leslie
L
D000818:Animals; D001554:Benzene / Q000493:pharmacokinetics / Q000633:toxicity*; D001854:Bone Marrow Cells / Q000187:drug effects / Q000473:pathology; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D004247:DNA / Q000187:drug effects; D004249:DNA Damage; D005260:Female; D020022:Genetic Predisposition to Disease; D006402:Hematologic Diseases / Q000139:chemically induced / Q000473:pathology; D008658:Inactivation, Metabolic / Q000235:genetics; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000201:enzymology; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D004247:DNA; D019392:Cytochrome P-450 CYP2E1; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; D001554:Benzene