Environmental and Molecular Mutagenesis - Legacy Tobacco ...

4 1989 EMS Abstracts
http://legacy.library.ucsf.edu/tid/clb93d00/pdf
Notes U•68,5538 is a novel drug under development by The Upjohn Company . This compound was marginally
positive in the Ames assay In the presence of S•9 and in In vitro cytopenetics in CHO cells In the absence of S-
9 . The result of testing in the In vitro UDS assay In rat hepatocytes was a clear positive . The compound was
not mutagenic in the mouse micronucleus test and was negative in both the CHO/HPRT and ASS2/xvRT
mammalian cell mutation assays . A variety of follow-up studies has revealed that the In vitro findings
probably do not reflect a 9enotoxic hazard . For exampie, no evidence of Induction of chromosome
aberrations in vivo was observed In rat bone marrow . Furthermore, the kinds of aberrations Induced In vitro
were primarily chromosome breaks and appeared to occur selectively in a few chromosomes . We followed
up this observation by G-bsndinq the chromosomes and determining the distribution of breaks in the
9enome . In fact, approximately 90% [207/234) of all the chromosomal aberrations were breaks in the three
longest chromosomes in the complement, with a larye majority in Chromosome 3. These breaks appear to
occur at discrete locations In the chromosomes that are broken . Finally, the In vitro UDS findings were
pursued by treatment of rats In vivo (the so-called "in vivolin vitro UDS") and there was no UDS observed In
vivo . Thus, the genetic toxicology profile of U-68,S63t yields several positive In vitro findings which are not
relevant to In vivo hazard . The assessment of risk due to this compound is clearly an example of the need for
rational risk assessment when in vitro tests give positive results . The full data and evaluation of the results
will be presented in the context of the risk assessment .
IN VIVO GENOTOXICITY OF CHEMICALS WHEN ADMINISTERED IN DIPPERENT SOLVENT/CARRIERS .
N .G . Abbott and A .F tlcFee, Oak Ridge Associated Oniversities, Oak Ridge, TN (USA)
Soae ehemieal coapounds to be tested for mutagen/eareinogen potency are insoluble in
both the aqueous and oil solvents eomaonly used for in vivo adainistration . Diaethyl
sulfoxide (DMSO) has often been used for injecting such compounds, but its in vivo
behavior and possible interaetion with the solute have besn questioned . We quantified
sister ehroaatid exchanges (SCE) in marrow leukoeytes and aieronuelei (MN) in
polychromatic erythrocytes (pCE) of mice after injections of compounds having various
degrees of solubility in phosphate-buffered saline (PBS), corn oil (00), and DHSO .
Equal quantities of chemicals were adainistered as solutions or mechanical suspensions
in each of the carriers, and aice vsre killed 24 hr later . SCEs were scored in 25
metaphases from each of 4 mice psr treatment, and fluorescence microscopy was used to
enuoerate MN among 2,000 FCE in each of 5 aice per treatment . SCEs induced by 10mg/kg
of 7,12-diaethylbensanthracene (DqBA) were significantly higher when administration was
in CO solution than in PBS suspension, and even higher when in DNSO solution . MN
induction was significantly higher following administration of 50 ag/kg of DMBA in OD
or DMSO solutions than with PBS suspension . The number of SCE induced by
diglycidylresorcinol ether showed a relationship to ita solubility in the various
carriers, whereas MN induetion was increased most sharply when injeetions were in DMSO .
Doses of 1,2-dibroao-3-chloropropane in DNS0 solution repeatedly produced much higher
nuabers of SCE than the same amounts given in CO solution or PBS suspension . The data
identify some compounds which express greater genotoxicity when administered in DpSO
solution and some with a possible chemical interaction with DdSO . Supported by NIEBS
Interagency Agreement Y01-ES-20100 and DOE/0RA0 Contract DE-ACOS-760R00033 .
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METABOLIC ACTIVATION OF Me1Q TO A MUTAGEN BY HEPATIC PREPARATIONS FROM DIFFERENT RAT
STRAINS . Amal Abu-Shakra, Cellular and Genetic Toxicology Branch, National Institute
of Environmental Health Sciences, Research Triangle Park, MC 27709 .
MeIQ (2-amino-3,4-dimethylimidazo[4,5-f]Quinoline) was activated to a mutagen in
the Ames test by hepatic microsomal preparations from Aroclor- pretreated Mistar .
Sprague-Dawley and Fischer rats . NeIQ-Rwtapenicity was catalysed by cytochromes P448,
which are induced by Aroclor . Microsomes from the uninduced rats were deficient In
the cytochromes P448 and could not activate MeIQ . Purified microsomes from induced
rats, regardless of the strain, activated MeIQ to give 860-920 rev/ng . This strong
mutagenic response was enhanced when the microsomes were supplemented with their
respective cytosolic fractions, to generate the •resuspended• $9 . Strain differences
became apparent with this procedure . Resuspension caused Fischer-S9 to be noticeably
weaker than Wistar-S9 and Sprague-Dawley-S9 . Because the strains were similar in their
microsome-mediated responses, it seemed that differences in S9-activation could be
attributable to the cytosol . However, in a cross-over study, where the cytosol of one
strain was mixed with the microsomes of the other, Fischer-cytosol mixed with Wistaror
Sprague-Dawley-microsomes provided stronger MeIQ-activation than did Fischercytosol
with Fischer-microsomes . Also, Wistar-and Sprague-Dawley-cytosol, which were
excellent enhancers of their respective mlcrosane-mediated responses, failed to
enhance that of the Fischer-microsomes . Therefore, strain differences are not only due
to different levels of cytosolic activity, but are affected by tnteractions between
the cytosol and the microsome-generated metabolites .
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