Environmental and Molecular Mutagenesis - Legacy Tobacco ...

earlier separation of the centromeres wes also noticed . The clestogenicity and
cytotoxicity of the druge"was further substantiated by in vivo essays with mouse
bone marrow cells where it caused dose dependent increase of chromosomal aberrations,
sister chrometid exchanges and micronuclei . Hydracortisone, therefore,
appears to be highly potent steroidal drug capable of directly attacking the
genetic material inspite of its negative response in the Ames teat,
542
MUTAGENICITY IN SALMONELLA AND SISTER CHROMATID EXCHANGE IN MICE FOR BAY-REGION
SYAL AND ANTI-DIOL EPOXIDES OF 1,4-DIMETHYLPHENANTHRENE
J .E . Sinsheimerl . A .K . Gir11, E .A . Messerlyl, K-Y . Jung2 and M . Koreeda2,
1College of Pharmacy and 2Department of Chemistry, University of Michigan . Ann
Arbor, MI 48109, USA .
Dose-response relationships for (±)-7a,8s-dihydroxy-5p .6p-epoxy-1 .4-dimethyl-
5,6,7,8-tetrahydrophenanthrene and its Sa,Ba-epoxy diastereomer, the syn- and
anti-diol epoxides of 1,4-dimethyl-phenanthrene respectively, have been tested
for their mutagenicity In Salmonella strains TA98 and TA100 and for their In vivo
sister chromatid exchange In the bone-marrow cells of mice . Both isomers were
mutagenic In the nmole per plate range with the syn isomer being In the order of
fifteen times more active with TA98 and five times more mutagenic In TA100 than
its anti isomer . The anti lsomer was more genotoxic In the sister chromatid
exchange assay than the syn isomer . Stetistically significant results were
obtained as low as 1 .5 mg/kg body weight for the anti isomer and 3 mg/kg for the
syn isomer . The present study supports the inclusion of methyl-substituted bayregion
diol epoxides In the concept that the syn isomer, with quasi-diequatorial
hydroxyl groups, contributes to the genotoxicity of the parent polycyclic
aromatic hydrocarbons of those compounds which form hindered bay-region diol
epoxides . Supported by grants R01ES0334S . NIEHS and R01CA25185, NCI .
543
THE ROLE OF PROTEIN ADDUCTS IN THE STUDY OF CHEMICAL CI4RCINOGENESIS . P . L . Skipper
and S . R . Tannenbaum, Massachusetts Institute of Technology, Cambridge, MA 02139 .
The reaction of carcinogens with proteins is an incidental but apparently inevitable
outcome of the process of metabolic activation to ultimate carcinogens ; thus far no
etiological role has been ascribed to these adducts . Nevertheless, they provide an
excellent historical record of exposure and subsequent metabolic events which may be
exploited to several ends . Firstly, they may be productively used in exposure
assessment . In this category fall such applications as exposure monitoring, definition
of exposed populations, and identification of cryptic exposures . Cigarette smoking,
as well as exposure to environmental tobacco smoke, have been monitored by analysis
of hemoglobin-bound 3- and 4-aminobiphenyl . These studies also demonstrated that
cigarette smokers are a distinct group defined by five- to ten-fold higher adduct
levels than nonsmokers . Similar evaluation of the contribution of cigarette smoking
to benzo[a7pyrene exposure has been conducted . Secondly, protein adducts are useful
in assessing the role of individual differences in biochemical response within a
population exposed to relatively similar amounts of a carcinogen . Thus, hemoglobin
adducts of 4-aminobiphenyl in smokers have been used to assess the significance of
acetylator phenotype on the activation of this carcinogen through hydroxylamine
formation . Finally, subject to many caveats, protein adducts have the potential for
improving assessment of risk . Factors which affect the feasibility of realizing this
potential will be discussed . This work was supported by the National Institutes of
Health (grant nos . ESO0597, ES02109, ES01640) and the American Cancer Society (grant
no . SIG 10-II) .
544
CORRELATION OF DNA ADDUCTS WITH SPECIFIC ALTERATIONS IN DNA SEQUENCEt IMPLICATIONS FOR
CANCER RESEARCH . T .R . Skopek . Chemical Industry Institute of Toxicology, Research
Triangle Park, NC (USA)
A variety of DNA alterations have been observed in the activation of oncogenes and
the inactivation of tumor suppressor genes . These include point mutations in protein
coding regions, point mutations affecting aRNA splicing, gene rearrangements, gene
amplification, and losa of hemisygousity . Molecular biology techniques are presently
being used to learn how different chemical mutagens can effect these specific
alterations in DNA . Knowledge of the DNA adducts and sequence alterations induced by
chemical mutagens'permits the correlation of specific adducts with specific mutations ;
this in turn can be used to infer a mutagen's ability to effect specific base changes
commonly associated with oncogene/suppressor gene alterations . Once identified,
http://legacy.library.ucsf.edu/tid/clb93d00/pdf
1989 EMS Abstracts 187
Notes
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