Journal Article

Critical role of allyl groups and disulfide chain in induction of Pi class glutathione transferase in mouse tissues <i>in vivo</i> by diallyl disulfide, a naturally occurring chemopreventive agent in garlic

Chhanda Bose, Jianxia Guo, Ludwika Zimniak, Sanjay K. Srivastava, Sharda P. Singh, Piotr Zimniak and Shivendra V. Singh

in Carcinogenesis

Volume 23, issue 10, pages 1661-1665
Published in print October 2002 | ISSN: 0143-3334
Published online October 2002 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/23.10.1661
Critical role of allyl groups and disulfide chain in induction of Pi class glutathione transferase in mouse tissues in vivo by diallyl disulfide, a naturally occurring chemopreventive agent in garlic

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We have shown previously that the chemoprotective activity of diallyl disulfide (DADS), a naturally occurring anticancer agent in garlic, against benzo[a]pyrene (BP)-induced forestomach carcinogenesis in mice correlates strongly with its inductive effects on the expression of Pi class glutathione (GSH) transferase mGSTP1-1. The present structure–activity relationship studies were designed to define the role of allyl groups and the disulfide chain in mGSTP1-inducing activity of DADS. Hepatic mGSTP1 mRNA levels rose rapidly upon treatment of mice with DADS, reached a maximum between 12 and 24 h (≤5.7-fold induction) and fell to control levels by 48 h after DADS treatment. Induction of mGSTP1 mRNA in the forestomach was maximal between 6 and 12 h after DADS treatment (≤4.7-fold induction). The mGSTP1 mRNA expression was either unaltered (liver) or moderately increased (forestomach) upon treatment of mice with dipropyl disulfide (DPDS), which is a naturally occurring saturated analog of DADS. These results indicated that the allyl groups are critical for the mGSTP1-inducing activity of DADS. A statistically significant increase in the expression of mGSTP1 mRNA was also observed in the liver and forestomach of mice treated with diallyl monosulfide (DAMS), albeit to a much lesser extent compared with DADS. These results indicated that the oligosulfide chain length in garlic organosulfides (OSCs) is equally important for their mGSTP1-inducing activity. The role of the disulfide chain in DADS-mediated induction of mGSTP1 was further investigated by testing a pair of alkadienes (1,7-octadiene and 1,8-nonadiene) having structural similarity to DADS. Both DADS and the alkadienes carry allyl groups at both ends of a linear molecule and the distance between the allylic carbon atoms is similar in both compounds, but the central disulfide chain of DADS is replaced with an alkyl chain in the alkadienes. The alkadienes were either ineffective or moderately active in increasing mGSTP1 expression. In conclusion, the results of the present study clearly indicate that the presence of terminal allyl groups as well as the central disulfide chain is required for maximum induction of mGSTP1 in vivo by garlic-derived OSCs.

Keywords: BP, benzo[a]pyrene; (+)-anti-BPDE, (7R,8S)-dihydroxy-(9S,10R)-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene; DADS, diallyl disulfide; DAMS, diallyl monosulfide; DAU, diallyl urea; DPDS, dipropyl disulfide; GSH, glutathione; mGSTP1-1, Pi class murine glutathione transferase isoform; 1,7-OD, 1,7-octadiene; 1,8-ND, 1,8-nonadiene; OSCs, organosulfur compounds.

Journal Article.  3734 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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