Environmental and Molecular Mutagenesis - Legacy Tobacco ...

259 1989 EMS Abstracts
THE INDUCTION OF CHROMOSOME ABERRATIONS IN MOUSE BONE MARROW AND CH0 CELLS BY THE DNA Notes
TOPOISOMERASE INHIBITORS CAMPTOTHECIN AND m-AMSA . D .R . Hovardl L .C . Backerl, J .A .
Campbelll, D .M . DeMarini2, J .W . Allen2, 1EHRT, RTP, NC 27709 ; 2U .S . EPA, RTP, NC 27711 .
Topoisomerases are enzymes that control supercoiling, breakage, and reunion of DNA
strands . There is evidence to suggest that two antitumor drugs, camptothecin (CAMP)
and amsacrine (ID-ANSA), inhibit topoisomerase activity by binding to the DNAtopoisomerase
complex and preventing reunion of the broken DNA strands . a-AMSA binds
to topoisomerase II to induce double-strand breaks in DNA . CAMP inhibits the activity
of topoisomerase I, inducing single-strand DNA breaks . Although y-AMSA induces
chromosome aberrations (CAs), CAMP has not been characterized for this effect . In the
present experiments, CAMP and m-AMSA were compared for their capacities to induce
chromosome- and chromatid-type aberrations in mouse bone marrow and CH0 cells . Male
mice were exposed by i .p . injection to 0, 0 .5, 1 .5, or 3 .0 mg/kg of CAMP or a-AMSA
dissolved in DMSO . Four animals/dose and 100 cells/animal were scored for CAs . Both
chemicals induced approximately 50 chromatid-type and 10 chromosome-type aberrations
per animal at the highest dose . CHO cells were incubated in medium containing either
CAMP or g-AMSA at 0, 10, 50, or 100 ng/ml in 0 .5% DMSO . Cells were harvested at 16-18
h and 100 cells/dose scored for CAs . At 100 ng/ml, a-AMSA induced 0 .56 chromatid-type
and 4 .95 chromosome-type aberrations/cell ; CAMP induced 0 .44 chromatid- and 1 .33
chromosome-type aberrations/cell . In summary, jD vivo analyses did not reveal
qualitative or quantitative differences in clastogenic activity between a-AMSA and
CAMP ; both induced predominantly chromatid-type aberrations . In contrast, both
chemicals induced more chromosome-type aberrations jn vitro ; ID-AMSA was more potent
than CAMP in producing this effect . (Seis .bsts .et do.s aet n.e.. . .rily r .fl.ct U .S . eM youey .)
260
METABOLISM AND MUTAGENICITY OF 1-NITROPYRENE, 3-NITROFLUORANTHENE AND
1,8-DINITROPYRENE IN SELECTED STRAINS OF SALMONELLA TYPRIb1URIUM. Paul C .
Howard and Elena C . McCoy, Department of Environmental Health Sciences, Case
Western Reserve University School of Medicine, Cleveland, OH (USA) 44106
The metabolism of three nitrated polycyclic aromatic hydrocarbons (1nitropyrene,
3-nitrofluoranthene, 1,8-dinitropyrene) were determined in selected
derivatives of the Salmonella typhimurium bacteria used in the widely used
reversion assay (TA98, TA98/1,8DNP6, TA100, TA100NR, Tn5-1012), and contrasted to
the mutagenicity of the chemicals in these bacteria. As expected, only
nitroreductive metabolism was detected with the three chgmicals . In all cases, the
nitroreductive metabolism of 3-nitrofluoranthene and 1,8-dinitropyrene were twice
the rate of the metabolism of 1-nitropyrene. The lack of mutagenicity of several
of the chemicals in some of the bacteria do not correlate with nitroreduction, and
can be attributed to the loss of the bacterial arylhydroxylamine O-esterificase .
However, in several other cases, the loss of mutagenicity of chemicals is apparently
caused by differing expressions of multiple nitroreductases . Supported in part by
grant ES-03648 from the NIH .
261
IN VITRA ASSAYS OF IN VIW E}PCSURE TO CY=PHOSPFm!-IIDE AND BENZO(a)PYItENE : INDCK,TIGN
OF SISTER-C3ffZ0IWZD E}OQHANGE4 CF HUMAN PERIPIERAL LYMPHOCYRFS BY CHElffCT+L E7lPOBID
NOUSE BIOOD
You-Chiu Hu, M .D. and Lia Ping
Cancer Research Lab ., Hunan Medical University, Charr3sha 410078, P .R. China
A method was devised to assay the genotoxic potential of cycLophosphmnide (CY)
and benzq7yrene (BP) . Mice were exposed to different doses of CY and HP, blood from
the drug-exposed mice was added to human ly::phocyte cultures and the sister clu-emstic
exc'ianges (SCE) of 1ymPlxx.ytes were assayed . CY at doses of 0 .2, 0 .4, and 0 .8 mM,
BP at doses of 0 .08, 0 .16 and 0 .32 mM were ip injected to mice . 20 minutes post ip
injection, 0 .4 ml blood fran each exposed m0use was added to a phyt9henagglutinin
(PHA) stimulated human lymphoc.yte culture and the SCE's of human 1ynQhocytss were
assayed . Normal saline or D6ND was ip injected as zero dose . In the control group,
CY and BP at different doses were added directly to the PHA-stimulated human lytsphocyte
cultures oontai .cting Brdurd . Exposed mouse blood induoed a dose-dependent SCE
increase in hunan lymphocytes at all tested doses . The CY tested group, the increase
of SCE/cell over base line were : 0 .2mM, 19 .81 ; 0 .4 mN1, 41 .97 ; 0 .8mM, 66 .74 . BP
treated group showed similar results : 0 .8mM, 23 .06 ; 0 .16mN., 34 .30 ; 0 .32 mM, 55 .62,
indicating the presence of direct-acting SCE-in8uciry metabolites of CY and BP in
r.ice blood . in both control groups, the increase of SCE were nsgligible . This
In Vi',tb assay-In VIvO exposure technique may be a simpl,e and useful system for
assaying the In Vivo genotoxicity of a chetnical .
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