Environmental and Molecular Mutagenesis - Legacy Tobacco ...

1989 EMS Abstracts
and then 5-fold into culture dishes . Cultures were incubated 28-days and evaluated Notes
for the presence of Types I-III foci . All experiments were conducted in the sene
of any exogenous activation system . Seventy carcinogens and 58 noncareinoaens were
tested in two or more transformation experiments . Carcinogens included 43 chemicals
that were relatively cytotoxic to the BALB/c-3T3 cells (LD < 2 .0mM), and 27 noncvtotoxic
chemicals (LOse > 2 .0mM) . Similarly, noncarcinogens included 27 cytotoxic
chemicals and 31 noncytotoxic chemicals . All chemicals were evaluated at cytotoxic
treatment doses . Transforming activities of the 128 chemicals will be compared to
their reported structural alerts and flenotoxic activities in four in vi r assays :
including Salmonella, mouse lymphoma (TK+/-), and Chinese hamster ovary sister chromatid
exchanges and chromosomal aberrations . Chemieal-induced activities detected
in the presence and absence of an S9 activation system will be discussed separately .
Experimental investigations were supported by NIEHS Contract N01-ES-65150 .
359
TISSUE SPECIFICITY OF THE MUTAGENICITY OF 1,8-DINITROPYRENE IN A MOUSE-MEDIATED
ASSAY . M .A . McCartney, S . Knasmfiller, E .C . McCoy and H .S . Rosenkranz, Department of
Environmental Health Sciences, School of Medicine, Case Western Reserve University,
Cleveland, Ohio 44106 .
1,8-Dinitropyrene (1,8-DNP) is a highly mutagenio environmental contaminant which
is also carcinogenic to rodents . DNA adduct formation, mutagenioity and presumably
carcinogenicity are dependent upon nitroreduction to the corresponding
arylhydroxylamine followed by 0-esterification by a transacetylase . Bacteria
(Salmonella typhimuriurn TA98/1,8-DNPs) deficient in this transacetylase do not
exhibit mutagenicity when exposed to 1,8-DNP . In a mouse-mediated assay (MMA) 1,8-DNP
induced mutations in S . typhimurium TA98 recovered from liver and spleen of treated
animals . However, when the MMA was performed using S . typhimuriurn TA98/1,8-DNPa 1,8-
DNP-induced mutants could be recovered only from the spleen but not from the liver .
The relevance of these findings to the tissue-specificity of 1,8-DNP will be
addressed .
360
MALIGNANT TRANSFORMATION OF HUMAN FIBROBLASTS BY• ONCOGENE TRANSFECTION OR
CARCINOGENS. J .J . McCormick and V .M . Maher, Carcinogenesis Laboratory, Michigan
State University, East Lansing, MI 48824 (USA)
Data indicate that carcinogen exposure is the cause of most human tumors, but
human cells in culture have not been successfully transformed to malignancy by
exposure to chemical carcinogens or radiation . One possible explanation for this
failure is inability to recognize the phenotypes of carcinogen-treated cells that
have undergone intermediate changes, so they can be expanded and exposed a second
time to cause further changes . To Identify possible intermediates, we transfected
diploid human fibroblasts with oncogenes known to be active in cells derived from
fibrosarcomas and determined the phenotypes they produced . H- or N-ras oncogenes
flanked by suitable enhancer and promoter sequences caused the celfs to acquire
many characteristics of malignant cells, but not to acquire an infinite life span
or form tumors . When we transfected these ras oncogenes in the same constructions,
or a viral K-ras oncogene, into an infinite -Me span, near-diploid, non-tumori genic
cell strain developed in this laboratory (MSU-l .l cells), distinct foci of
morphologically-altered, anchorage independent, and growth factor independent cells
were found which formed progressively-growing, invasive malignant sarcomas in athymic
mice . These cells expressed the p2ls of the transfected ras genes . Transfection
of two other infinite life span human cell lines with the~T-ras oncogene in the
same construction also yielded malignant cells . We are currenETy using carcinogen
treatment to activate cellular proto-oncogenes of the MSU-1 .1 cells and have
succeeded in malignantly transforming cells . (Supported by DOE Grant 60524, NCI
Grant CA21289 and NIEHS Contract ES65152 .)
361
HEPATIC AND LUNG MICROSOMAL METABOLISM OF ENVIRONMENTAL POLLUTANTS : EFFECTS OF !!1
INDUCER PRETREATMENT ON THE METABOLISM OF 1-NITROPYRENE, 3-NITROFLUORANTENE AND m
NICOTINE . 00
G .D . McCoy , D . R . Koop and P . C . Howard, Case Western Reserve University, School of
Medicine, Cleveland, OH 44106 tp
The ability of microsomes isolated from adult male and female New Zealand
rabbits to metabolize 1-nitropyrene (i-NP) , 3-nitrofluranthene (3-NF) and nicotine W
(N) has been studied . Hepatic and lung microsomes were isolated from animals 01
pretreated with either 1-nitropyrene, P-napthoflavone (J)-nf) or phenobarbital (Pb). W
J
The C-oxidation of 1-NP, 3-NF and N were significantly increased only in mlcrosomes
from phenobarbital pretreated animals . In contrast, both Pb and 0-nf pretreatment
significantly decreased the rates of nicotine N'-oxidation . Our previous studies
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