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Bartsch 1978
Bartsch 1978
H. BARTSCH 1, T K U R O K I 1, C M A L A V E I L L E 1, N LOPRIENO 2, R. B A R A L E 2,
A. A B B O N D A N D O L O 3, S. B O N A T T I 3, G R A I N A L D I 3, E. VOGEL 4 and A. DAVIS s
Summary
Introduction
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138
quantel did n o t increase the number of reverse mutations to his*, either in the
presence or absence of an S-9 hver fraction from rats or mice pretreated with
either MC, Aroclor or combined MC and PB. As Praziquantel has an aromatic
ring which could be oxidized by microsomal mono-oxygenases to yield reactive
arene oxides, we tried to inhibit their hydration to dihydrodiols. 1,1,1-Tn-
chloropropene-2,3-oxlde is such an inhibitor of mmrosomal epoxide hydratase
and potentiates the mlcrosome-mediated mutagenlcity of polycychc hydrocar-
bons [27]. Its addition at a concentration of 0.4 mM to plates contmnmg the
TA98 strain and S-9 liver fractions from rats or mice pretreated with MC or
Aroclor did n o t increase the number of his+ revertant colonies.
Praziquantel, at a concentration of 5 mM did n o t increase the number of
forward mutations in S. p o m b e (Pl-straln) at 5 adenine loci (Expt. 3) after 4-h
incubation m the presence of an S-9 mouse-hver fraction. Similarly, no mitotic
gene conversions at the ade 2 or trp 5 loci were induced in S. cerevzsiae, D4
strain (Expts. 4--7), in the presence of an S-9 mouse-liver fraction for 4 h or in
the absence of an activation system for 24 h incubation with a concentration of
10 mM Praziquantel, although a concentration of 0.5 mM h y c a n t h o n e at pH
6.5 increased the conversion frequency to 10 times the spontaneous level at the
two genetic loci d u n n g a 6-h Incubation period.
In the host-mediated assay in mice (Expts. 8--10), Prazlquantel at 600 mg/kg
bw did n o t produce a statistically signlfmant increase in the frequency of for-
ward mutations in S p o m b e or of gene conversions in S. cerevisiae following
1.v. Injection of the yeast cells (results from 2 experiments are listed).
Unscheduled incorporation of 3H-TdR, in the presence of h y d r o x y u r e a to
suppress DNA replication, was used to estimate DNA repair synthesis in a cul-
tured human heteroploid cell line (EUE) (Expts. 11,12). Dunng 1 h of incuba-
tion, up to a 5 mM concentration, Praziquantel, in the presence or absence of
an S-10 mouse-hver fraction, induced no DNA lesions t h a t led to DNA-repmr
synthesis; whereas 1 mM hycanthone, in the absence of an S-10 liver fraction,
increased the incorporation of 3H-TdR 3 times over the control level.
No slster-chromatid exchanges (Expts. 13, 14) were induced in cultured V79
Chinese hamster cells in the presence or absence of an S-10 mouse-hver frac-
tion, at concentrations up to 1 mM PrazIquantel during 2 h of incubation.
Under these conditions, 0.1 mM hycanthone increased the number of sister-
chromatid exchanges per metaphase to 7 times the spontaneous level.
A concentration of up to 3 mM Praziquantel did n o t induce 6-thloguanme-
resistant mutants in V79 Chinese hamster cells (Expts. 15, 16) during 1 h of
treatment e~ther in the presence or absence of an S-10 mouse-hver fraction,
1 mM h y c a n t h o n e increased the mutation frequency 60-fold over the sponta-
neous level.
The mutageniclty of Prazlquantel was also examined in V79 Chinese hamster
cells in the presence of an S-15 liver fractmn from phenobarbitone-pretreated
rats (Expts. 17--20) and in cell-mediated assays (Expts. 21--24), by the use of
mutations to 8-azaguanine and ouabam resistance. In the microsome-mediated
assay, exposure to up to 1 mM PrazIquantel for 3 h induced no toxmlty and no
azaguanme- or ouabmn-reslstant m u t a n t colonies. Polycychc hydrocarbons are
more effmiently detected as mutagens in cell-mediated assays whereby V79
Chinese hamster cells are co-cultwated with lethally irradiated rodent emb~,o
140
Acknowledgements
References