TY - JOUR
T1 - Gender-related differences in susceptibility of A/J mouse to benzo[a]pyrene-induced pulmonary and forestomach tumorigenesis
AU - Singh, Shivendra V.
AU - Benson, Patrick J.
AU - Hu, Xun
AU - Pal, Ajai
AU - Xia, Hong
AU - Srivastava, Sanjay K.
AU - Awasthi, Sanjay
AU - Zaren, Howard A.
AU - Orchard, John L.
AU - Awasthi, Yogesh C.
N1 - Funding Information:
This investigation was supported in part by US PHS grants CA55589 (to S.V.S.), CA27967 (to Y.C.A.) and CA63660 (to S.A.) awarded by the National Cancer Institute. The financial support of The Pittsburgh Foundation (Jacob A. and Frieda M. Hunkele Charitable Trust) is also acknowledged.
PY - 1998/6/19
Y1 - 1998/6/19
N2 - Benzo[a]pyrene (BP) is a suspected human carcinogen and is known to produce tumors in the lung and forestomach of mice. Glutathione (GSH) S-transferases (GST) play a major role in the detoxification of the ultimate carcinogen of BP, (+)-anti-7,8-dihydroxy-9,10-oxy-7,8,9, 10-tetrahydrobenzo[a]pyrene ((+)-anti-BPDE). Previous studies have shown gender-related differences in the expression of GST isoenzymes in mice. The present study was designed to test the hypothesis whether gender-related differences in the expression of GST isoenzymes can affect the susceptibility of mice to BP-induced lung and forestomach tumorigenesis. The expression of Π class isoenzyme mGSTP1-1, which is highly efficient in the detoxification of (+)-anti-BPDE, was approximately 3.0- and 1.5-fold higher in the liver and forestomach of male A/J mouse, respectively, as compared with the female. The levels of other major GST isoenzymes, mGSTA3-3 (α class), mGSTM1-1 (μ class) and mGSTA4-4 (α class), were also significantly higher in the liver of the male mouse as compared with the female. While pulmonary mGSTP1-1 expression did not differ significantly between male and female A/J mice, the expression of mGSTA3-3, mGSTM1-1 and mGSTA4-4 was significantly higher (1.4-4.0-fold) in the lung of the male A/J mouse as compared with the female. At lower concentrations of BP (0.5 mg BP/mouse), the tumor incidence/multiplicity was significantly higher in the lung as well as in the forestomach of female mice as compared with male mice. For example, while 30% of the female mice developed pulmonary tumors 26 weeks after the first 0.5 mg BP administration, none of the male mice had tumors in their lungs. At higher doses of BP (1.5 mg BP/mouse), however, this differential was either abolished or relatively less pronounced. Our results suggest that up to a certain threshold of BP exposure the levels of GST isoenzymes may be an important determinant of susceptibility to BP-induced tumorigenesis in mice.
AB - Benzo[a]pyrene (BP) is a suspected human carcinogen and is known to produce tumors in the lung and forestomach of mice. Glutathione (GSH) S-transferases (GST) play a major role in the detoxification of the ultimate carcinogen of BP, (+)-anti-7,8-dihydroxy-9,10-oxy-7,8,9, 10-tetrahydrobenzo[a]pyrene ((+)-anti-BPDE). Previous studies have shown gender-related differences in the expression of GST isoenzymes in mice. The present study was designed to test the hypothesis whether gender-related differences in the expression of GST isoenzymes can affect the susceptibility of mice to BP-induced lung and forestomach tumorigenesis. The expression of Π class isoenzyme mGSTP1-1, which is highly efficient in the detoxification of (+)-anti-BPDE, was approximately 3.0- and 1.5-fold higher in the liver and forestomach of male A/J mouse, respectively, as compared with the female. The levels of other major GST isoenzymes, mGSTA3-3 (α class), mGSTM1-1 (μ class) and mGSTA4-4 (α class), were also significantly higher in the liver of the male mouse as compared with the female. While pulmonary mGSTP1-1 expression did not differ significantly between male and female A/J mice, the expression of mGSTA3-3, mGSTM1-1 and mGSTA4-4 was significantly higher (1.4-4.0-fold) in the lung of the male A/J mouse as compared with the female. At lower concentrations of BP (0.5 mg BP/mouse), the tumor incidence/multiplicity was significantly higher in the lung as well as in the forestomach of female mice as compared with male mice. For example, while 30% of the female mice developed pulmonary tumors 26 weeks after the first 0.5 mg BP administration, none of the male mice had tumors in their lungs. At higher doses of BP (1.5 mg BP/mouse), however, this differential was either abolished or relatively less pronounced. Our results suggest that up to a certain threshold of BP exposure the levels of GST isoenzymes may be an important determinant of susceptibility to BP-induced tumorigenesis in mice.
KW - Benzo[a]pyrene
KW - Cancer susceptibility
KW - Chemical carcinogenesis
KW - Detoxification
KW - Glutathione transferase
UR - http://www.scopus.com/inward/record.url?scp=0032547128&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0032547128&partnerID=8YFLogxK
U2 - 10.1016/S0304-3835(98)00072-X
DO - 10.1016/S0304-3835(98)00072-X
M3 - Article
C2 - 9683283
AN - SCOPUS:0032547128
SN - 0304-3835
VL - 128
SP - 197
EP - 204
JO - Cancer Letters
JF - Cancer Letters
IS - 2
ER -
