Environmental and Molecular Mutagenesis - Legacy Tobacco ...

448 ' r 1989 EMS Abstracts 155
VITAMLN C INTAKE DECRKAS .ES CHROMOSOME DAMACE IN GENETIC INSTABILITY ASSAY
Pohl, H . and Reidv . J .1!
Genetics Branch, Division of Environm,mtal Health Laboratory Sciences, Center for
Environmental Health and Injury Control, Centers for Disease Control, Atlanta, CA
30333, USA
It has been suggested that some people are predisposed to cancer as a result
of genetic instability and this instability can be detected by exposing their cells
to a clastogen in vitro . We know very little, however, about person-specific
factors other than genetic instability sbat might influence this assay . We report
here that the amount of chromosome damage induced in human lymphocytes by an
exposure to bleomycin during the last 5 hours of cell culture significantly
decreased after the blood donors took 1 g of vitamin C per day for 2 weeks .
Similar changes were not seen in lymphocytes from control individuals sampled at
the same time but not taking vitamin C supplements . The initial study involved two
persons who took vitamin C and two controls who did not take the vitamin . Results
showed little variation among triplicate flasks and little variation over a month
in the controls . Results were confirmed in a second experiment with eight people
(p< 0 .01) . Each person was his own control . In addition, two laboratory controls
(individuals not taking vitamin C) showed no differences during the experiment .
From this limited study, we suggoet that it would be prudent to consider dietary
and perhaps other lifestyle factors in the interpretation of results from this and
related assays for genetic instability .
449
ORGAN SPECIFIC GENOTOXICITY AND CARCINOGENICITY B .L. Pool, P.Schmezer, A.
Tompa`, S.Y. Brendler. Institute for Toxicology and Chemotherapy, German Cancer
Research Center, INF 280, 6900 Heidelberg, FRG . 'National Institute of Occupational
Health, Nagyvarad T€r 2, Budapest, Hungary .
The factors governing the unique organ specific carcinogenic effects of Nnitrosamines
are largely unknown . Feasible mechanisms include (a) organ specific
metabolism (b) pharmacokinetics (c) peraistance of DNA damage. The role of each
pathway is being investigated for nitrosamines carcinogenic in hepatic or extrahepatic
tissues . Induced DNA single strand breaks were determined in primary rat cells of
liver, lung, kidney, testes, thymus gland and blood . (a) Organ specific metabolism was
not apparent in vitro using hepatocytes, since hepatotropic compounds were less
genotoxic than extrahepatic carcinogens . (b) PharmAcokinetics were monitored by
determining toxic and genotoxic effects in intact cells isolated from treated animals .
This approach has the advantage that DNA damage arising from toxicity can be
excluded, and that it is very sensitive . It was shown that < 1 mg/kg of the liver
carcinogen N-Nitrosodimethylamine is genotoxic in the liver ; > 2 mg/kg are active in
lung and kidney . No genotoxicity is detectable in cells of thymus gland or testes . (e)
Persistance of DNA damage was assessed after 1, 4, and 16 h exposure, and was
found to be greater in liver than in lung . Therefore, this compound's organ specificity
in carcinogenicity and in vivo genotoxicity agree well . This sensitive, versatile (multiple
organs), rapid (48 h) and efficient (few animals) in vivo method can identify tissues
which may be susceptible to carcinogenesis. The value of this approach to study
toxicokinetics of genotoxic compounds is stressed. Results with additional nitrosamines
and new approaches to monitor remote target organs will be presented .
450
GENETIC TOXICOLOGY OF THIAARENES B .L . Pool, P .Klein, P. Schmezer, S .Y. Brendler,
J.R. Schlehofer', and G. Grimmer", Institute for Toxicology and Chemotherapy,
`Institute for Virus Research, German Cancer Research Center, INF 280, 6900 Heidelberg,
°Institute for Biochemistry of Environmental Carcinogens, 2070 Grosshansdorf, FRG .
Three isomeric polycyclic aromatic sulfur heterocyclics (thiaarenes) have been
assessed for genotoxicity. An evaluation of thiaarenes is important, since they are
significant constituents of synthetic fuels . Compounds of this class may be structurally
similar to several carcinogenic polycyclic aromatic hydrocarbons, but they have not
been similarly well investigated for adverse biological effects . Benso(b)naphtho(2,1d)thiophene
is a sulfur-containing analog to chrysene and the other two isomers are
different by the position of their sulfur substitution (1,2-d and 2,3-d isomers) .
Following results were obtained : (a) In S . t,vphimurium TA98, mutagenic activity was
observed for 2 of the lsomers (2,1-d = 2,3-d; 1,2-d was negative) with standard
metabolic activation by S9 from Aroclor pretreated rats . Stimulation of the system for
glucuronyl acid conjugation did not reveal enhanced mutagenicity . (b) DNA Single
strand breaks were not observed in metabolically competent primary hepatocytes nor in
a Chinese hamster cell line. (c) Using the same cell line, integrated SV40-DNA was
shown to be amplified by two compounds (1,2-d ∎ 2,3-d; 2,1-d was not tested) . Results
of ongoing studies will be presented : (d) In a novel system, the amplification of Adeno-
Associated Virus DNA is being measured in primary Syrian hamster embryo cells (SHE)
http://legacy.library.ucsf.edu/tid/clb93d00/pdf
Notes