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Carcinogenesis |
Departments of Pathology and Biology of Diseases [Z-Z. Z., S. H., H. H.] and Gastroenterological Surgery [K. M.], Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto 606-8501, Japan; Department of Oncological Pathology, Cancer Institute, Nara Medical University, Kashihara 634-8521, Japan [W. K., A. D., Y. K.]; and Department of Biochemistry, School of Medicine, University of Occupational and Environmental Health, Kita-Kyushu 603-8555, Japan [Y. Y., K. H.]
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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-glutamyltranspeptidase mRNA
level. Furthermore, O6-methylguanine
DNA methyltransferase and mannose 6-phosphatase/insulin-like growth
factor 2 receptor mRNA levels were quantified. Composite interval
mapping analysis showed that there were two remarkably significant
clusters of quantitative trait loci affecting preneoplastic liver
lesions on chromosomes 1 and 4. These clusters were designated
collectively as Drh1 and Drh2,
respectively. The functions of the recessive DRH allele of
Drh1 and the semidominant DRH allele of
Drh2 were to suppress the phenotypes of precancerous
lesions. Each cluster showed two to three subpeaks in linkage
likelihood plots, suggesting the presence of several closely linked
quantitative trait loci affecting preneoplastic lesions. Possible
candidate genes at each locus will be discussed. Expression of
O6-methylguanine DNA methyltransferase and
mannose 6-phosphatase/insulin-like growth factor 2 receptor did not
affect DRH resistance to hepatocarcinogenesis, although they
were polymorphic between DRH and F344 rats. |
INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Genetic predisposition to chemically-induced liver cancers has been studied mainly in mice (as reviewed in Refs. 5, 6, 7 ). To date, about 10 loci have been mapped, but none of these have yet been cloned. Two rat strains, Copenhagen (8) and BN (9) , have been shown to be resistant to chemical induction of HCC. Recently, De Miglio et al. (10) mapped a set of BN QTL affecting the volume and/or volume fraction of HCC. These QTL consist of one susceptibility locus and at least three resistance loci. The consistent conclusion of these studies is that genetic predisposition to chemically induced HCC in rodents is a polygenic trait.
The inbred rat strain DRH was established from a closed colony of Donryu rats continuously fed 3'-Me-DAB and selected for reduced HCC induction during inbreeding for more than 10 years (11, 12, 13) . In contrast to carcinogen-susceptible parental Donryu rats, DRH rats showed a remarkably lower incidence of hepatic tumors when given liver carcinogens such as 3'-Me-DAB, DAB, 3'-ethyl-DAB, 2-acetylaminofluorene, 7,12-dimethylbenz(a)anthracene, or N-nitrosodimethylamine (14) . Such resistance is also evident in the induction of preneoplastic lesions. After 6–8 weeks of 3'-Me-DAB administration, Donryu rat liver showed more than 50-fold induction of the GST-P mRNA level above that of the untreated control, whereas DRH liver showed only 2–3-fold induction (15) . DRH resistance was suggested to be dominant because reciprocal DRH x F344 F1 rats are induced much less GST-P mRNA than F344 by short-term feeding of 3'-Me-DAB (15) . These characteristics indicated that the DRH rat may be a promising model in which to investigate host genetic control in hepatocarcinogenesis.
In this study, we explored the QTL negatively affecting 3'-Me-DAB-induced preneoplastic liver lesions in (F344 x DRH)F2 rats using number of EAF per unit area of liver section, the percentage area occupied by EAF, and the average size of EAF as quantitative parameters. Furthermore, mRNA levels of GST-P, GGT, MGMT, and M6P/IGF2R were quantified. Two clusters of DRH-derived QTL yielding resistance were mapped on RNO1 and RNO4 and designated as Drh1 and Drh2 (DRH resistance to hepatocarcinogenesis 1 and 2), respectively.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Animals and Treatments.
Inbred DRH and F344 rats were purchased from SEAC Yoshitomi,
Ltd. (Fukuoka, Japan) at 4 weeks of age and allowed to acclimatize for
1 week before use. F2 rats were generated by
intercrossing male and female (F344 x DRH)F1 rats. Starting at 5 weeks of age, male
F2 rats were fed a diet containing 0.06%
3'-Me-DAB for 8 weeks. All rats were housed individually in suspended
wire-bottomed cages in a room with a constant temperature of 24°C,
55% humidity, and a 12-h light (6 a.m. to 6 p.m.)/dark cycle. All
rats were sacrificed under ether anesthesia after 8 weeks of treatment,
and a full postmortem examination was carried out.
Histopathological Analysis.
Livers were removed, and 5-mm-thick slices were cut from the right
lateral median and right lateral lobes of individual rats. These slices
were fixed in ice-cold acetone and embedded in paraffin for subsequent
immunohistochemical examination of GST-P. Small pieces from the
remaining left lateral lobe of livers were quickly frozen and kept at
-80°C until RNA extraction. Paraffin-embedded blocks were sectioned
at a thickness of 3–4 µm and stained immunohistochemically for GST-P
by using the avidin-biotin peroxidase complex method (Vecstatin ABC
elite kit; Vector Laboratories, Burlingame, CA) as described previously
(16)
. For quantitative assessment of lesions, the areas of
liver sections and the numbers and areas of GST-P-positive foci,
i.e., EAF, were measured, and the numbers of
EAF/cm2 liver area and the percentage of liver
area occupied by EAF were calculated using an image analyzer (IPAP-WIN;
Sumika Technos Co., Ltd., Hyogo, Japan). Liver lesions were diagnosed
according to the criteria described by Squire and Levitt
(17)
and the descriptions given by the Institute of
Laboratory Animal Resources (18)
.
Northern Analysis.
Aliquots of 20 µg of total RNA extracted from individual liver pieces
by the guanidine isothiocyanate-phenol-chloroform procedure
(19)
were electrophoresed in 1.0% agarose gels and
transferred onto nylon membranes (Hybond N; Amersham Pharmacia Biotech,
Buckinghamshire, United Kingdom) prehybridized in a solution containing
4x SSC, 50% formamide, 0.5% SDS, 5x Denhardt’s solution, and 20
µg/ml salmon sperm DNA (20)
. The membranes were then
hybridized with a mixture of 32P-labeled
nick-translated probes of GST-P, GGT, MGMT, or M6P/IGF2R
(14)
at 42°C for 16–24 h. The membranes were washed in
1x SSC containing 0.1% SDS at 42°C for 30 min, and this was
repeated two or three times. The radioactivity on the hybridized
membranes was quantified using a BAS2000 bio-imaging analyzer (Fuji
Photo Film Co., Tokyo, Japan). To minimize data fluctuation between the
blots, 108 RNA samples were separated on 9 membrane filters and
hybridized with a single lot of radiolabeled probes on the same day.
Genetic Analysis.
For linkage analysis, we used the simple sequence repeat
(microsatellite) length polymorphism assay, using genomic DNA extracted
from the kidney as a template. All primers for microsatellite analysis
were purchased from Research Genetics, Inc. (Huntsville, AL.). Methods
for PCR and agarose electrophoresis of PCR products have been described
previously (21)
. The relative map positions of
microsatellite loci were based on Brown et al.
(22)
or obtained from the World Wide
Web.4
Of 536 microsatellite loci examined, 119 (22.2%) were polymorphic
between DRH and F344 and were readily recognizable on agarose gel
electrophoresis. To find the loci associated with either susceptibility
or resistance to preneoplastic liver lesions, 76 marker loci (2–14
markers for each chromosome) were analyzed. Approximate coverage was
94.6% of the entire rat genome, assuming that each marker would detect
linkage within a circle of 20 cM. Of 108 F2 rats,
we selected 20 each with extremely low or high GST-P or GGT mRNA levels
and percentage liver area occupied by EAF. A preliminary genome-wide
scan was performed by genotyping them for 66 markers. Linkage was
evaluated by 
2 test for goodness of fit
against an expected 1:2:1 ratio of F/F, F/D, and D/D genotypes (F
represents the F344 allele, and D represents the DRH allele). When a
marker locus showed a possible linkage (2
test, P < 0.05) in the primary screen, all
108 rats were genotyped for all available polymorphic loci on the same
chromosome. Any double recombinants were retyped to minimize typing
errors. Genotype data were analyzed using the Mapmaker/QTL program,
using five quantitative parameters for preneoplastic liver lesions.
When more than one possible peak of linkage was found on the
chromosome, composite interval mapping was carried out with
Cartographer QTL software (23)
to determine whether there
were multiple independent loci. In these analyses, two quantitative
parameters, GST-P and GGT mRNA levels, were transformed to logarithms,
and size of EAF was transformed to the square root to obtain a better
fit to the normal distribution.
Statistical Analysis.
In the preliminary genome scan, linkage was evaluated by the
nonparametric Kruskal-Wallis test. According to the criteria of Lander
and Kruglyak (24)
, linkage in the F2
generation was taken as significant when P was
<5.2 x 10-5 (lod score, 4.3)
and was suggestive when P was <1.6 x 10-3 (lod score, 2.8). Phenotypic differences
between the three genotypes (F/F, F/D, and D/D) were analyzed by the
unpaired Student’s t test. Correlations between different
phenotypic parameters were evaluated by correlation analysis with
StatView-J 4.11 software (Abacus Concepts, Inc., Berkeley, CA) on a
Macintosh personal computer.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Parameters of Preneoplastic Liver Lesions.
In this study, we focused on genetic control of preneoplastic liver
lesions after feeding rats 3'-Me-DAB for 8 weeks. First, five
phenotypic parameters that have been shown to be remarkably different
between DRH and other HCC-susceptible rat strains were selected
(14
, 15)
, i.e.: (a) the number of
EAF per unit area of liver section; (b) the percentage of
liver area occupied by EAF; (c) the average size of the
foci; (d) the GST-P mRNA level; and (e) the GGT
mRNA level. These parameters were closely correlated with each other,
as shown in Table 1
(r = 0.460–0.892). Therefore, none of them
seemed to be independent traits. The correlation between the number and
size of the EAF was just above the level of significance
(r = 0.460), whereas that between the number
of EAF and the percentage of liver area occupied by EAF was very high
(r = 0.892). GST-P and GGT mRNA levels both
correlated best with the percentage of liver area occupied by EAF,
suggesting that they were dependent on the total mass of EAF.
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.
These observations clearly excluded the possibility that
MGMT and M6P/Igf2R may be responsible for DRH
resistance.
QTL Analysis.
A preliminary genome-wide screen with 20 animals showing extremely low
and high phenotypic values revealed significant linkage on RNO1 and
RNO4 for all five parameters of preneoplastic liver lesions (data not
shown). Assuming a level of suggestive significance of
P < 1.6 x 10-3, no linkage for any of these phenotypic
parameters was suggested on other chromosomes. RNO2 and RNO18 contained
marker loci with 0.001 < P < 0.01.
Subsequently, we genotyped all 108 F2 rats for
the 27 microsatellite loci on RNO1 and RNO4, which were polymorphic
between DRH and F344.
The results of mapping were first analyzed by interval mapping with
MapMaker/QTL software (Fig. 1
). On RNO1 and RNO4, we observed three and two peaks, respectively.
Interval mapping by MapMaker/QTL assumes one locus/chromosome. To
further investigate whether these peaks represented independent QTL,
composite interval mapping with QTL Cartographer software (Version
1.13; Ref. 23
) was performed. Fig. 2
shows a linkage plot of the results of composite interval mapping.
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); we named this locus
Drh1a. At this position, the percentage area and mRNA levels
of GST-P and GGT formed a minor peak on interval
mapping (Fig. 1A
), but the peaks were below the level of
significance on composite interval mapping (Fig. 2A
). The
second peak was rather broad on the segment between D1Wox10
and D1Rat302. At the position of D1Rat302, lod scores for
the number of EAF, percentage area, and mRNA level of GST-P
were 8.0, 7.2, and 5.9, respectively. The lod score for the level of
GGT mRNA was below the level of significance (Fig, 2A);
it was designated as Drh1b. The third peak was linked
with D1 Mgh12. Although the presence of a quantitative trait
locus at this position was merely suggestive of the size of the EAF on
QTL Cartographer, we tentatively named it Drh1c because lod
scores for percentage area, GST-P mRNA, and size of EAF were above 4.3
in Mapmaker/QTL analysis. These three QTL/peaks were located close
together, and their phenotypic effects were pleiotropic. As
shown in Table 2
, at all three Drh1 loci, all genetic traits were recessive
because phenotypic values of F2 rats homozygous
for the DRH-derived allele were consistently smaller than those of rats
heterozygous and homozygous for the F344-derived allele.
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and 2B
). The first peak was closely
linked to D4Rat37, at which significant linkage was observed
for percentage area (lod score, 7.8), number of foci (lod score, 7.8),
mRNA level of GST-P (lod score, 4.6), and size of foci (lod score,
3.8). This locus was named Drh2a. The second peak
(Drh2b) was 4 cM distal from D4Rat48, at which
significant linkage was observed for percentage area (lod score, 5.8)
and number of EAF (lod score, 5.8). The interval between
Drh2a and Drh2b was as little as 10 cM,
but combination of the parameters showed that linkage to each loci was
different. The DRH allele of both Drh2a and Drh2b
was semidominant, as shown in Table 2
.
Cartographer QTL analysis showed that there were five putative QTL
affecting the parameters of precancerous lesions in (DRH x F344)F2 intercrosses. The map positions
of each locus were exactly the same as those suggested by Mapmaker
analysis. Each putative loci had pleiotropic effects on phenotypic
traits as seen in Table 2
. Fig. 3
shows the percentage of phenotypic variation explained by these loci.
The loci explaining >20% phenotypic variance for the number of EAF
were Drh1a, Drh1b, Drh2a, and Drh2b; those for
percentage area of EAF were Drh1a, Drh1b, Drh2a, and
Drh2b; and those for GST-P mRNA were Drh1b,
Drh2a, and Drh2b. For GGT mRNA, low peaks
of 
15% were observed at Drh1a and Drh1b. For
the size of EAF, similar low peaks of 15% were seen at
Drh1c and Drh2a.
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. They were,
however, located on RNO1, so that we performed QTL analysis of
these loci. The semidominant MGMT locus was mapped 8 cM proximal to
Drh1a with a lod score of 18.6 (data not shown). None of
five preneoplastic lesion traits were comapped at MGMT. Another
semidominant M6P/IgF2R locus was mapped on the short arm of
RNO1, very close to D1 Mit9 (data not shown). Again, none of
the five preneoplastic lesion traits were comapped with this
locus. |
DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. For preneoplastic liver lesions, five QTL were mapped by
composite interval mapping of 108 F2 rats.
Whether these loci are directly correlated with susceptibility to HCC
remains unclear, but answers to this question will soon be provided by
a concurrent study in our laboratory. DRH rats are resistant to a broad spectrum of chemical carcinogens: (a) DAB; (b) 3'-Me-DAB; (c) 3'-ethyl-DAB; (d) 2-acetylaminofluorene; and (e) N-nitrosodimethylamine (14) . To explain the mechanism of resistance, the biochemical pathway of 3'-Me-DAB has been studied extensively. The level of metabolic activation of DAB is lower and the level of metabolic inactivation of DAB is higher in the DRH rat liver than in the parental Donryu rat liver (14) . However, there is no difference in DNA-adduct formation of 3'-Me-DAB between the carcinogen-sensitive parental strain Donryu and carcinogen-resistant DRH rat livers at several time points during 3'-Me-DAB administration (14) . Therefore, the critical event of resistance in the DRH strain seems to occur after formation of DNA-adducts. In support of this hypothesis, we found that the expansion of EAF in the DRH rat liver after 3'-Me-DAB administration was significantly less than that seen in Donryu rats under the same experimental conditions (15) . The target of resistance was not specific to the liver because DRH females given 7,12-dimethylbenz(a)anthracene were highly resistant to mammary cancers (14) .
In this study, we used F344 rats as 3'-Me-DAB-sensitive parents rather
than Donryu rats. This was because the parental Donryu strain was not
inbred but was a closed colony. Multiple QTL affecting preneoplastic
liver lesions were mapped in the (F344 x DRH)F2 intercross rats. None of the phenotypic
traits was controlled by a single quantitative trait locus. All QTL
were pleiotropic and formed clusters on RNO1 and RNO4. It was not
possible to separate them clearly by likelihood plots, even by
composite interval mapping, and therefore they were tentatively
designated as Drh1a, Drh1b, and Drh1c and
Drh2a and Drh2b. Drh1a, Drh1b, and
Drh1c were localized on the distal segment of RNO1.
Drh1a was at the major peak of the linkage curve, especially
for the trait of number of EAF. The DRH allele of Drh1
reduced all phenotypic values in a recessive manner. At the position of
Drh1a, there are several putative candidate genes affecting
carcinogenesis: (a) c-Ha-ras; (b)
Hrev107; (c) Ins2; (d)
Igf2; (e) H19; (f)
Tapa1; and (g) Gst-p. The cellular
proto-oncogene c-Ha-ras is activated in mouse HCC induced by
chemical carcinogens (25, 26, 27)
but is activated relatively
infrequently in human HCC and rat HCC (28)
.
Hrev107 (29)
is a putative tumor suppressor
gene that inhibits the malignant phenotype of Ha-ras-transformed cells.
Other possible tumor suppressor genes are H19
(30)
and TAPA1 (31)
. The segment
containing Igf2 and H19 shows parental
imprinting. The observation that reciprocal DRH x F344
F1 rats are equally resistant to 3'Me-DAB
(15)
excluded Igf2 and H19
from being candidate genes. MGMT is one of the key enzymes
involved in DNA repair, and mice with targeted disruption of
MGMT are highly susceptible to carcinogen-induced HCC as
well as thymic lymphoma (32
, 33)
. DRH rats showed far
lower levels of MGMT induction than Donryu rats after
3'-Me-DAB feeding (14)
. MGMT was mapped only 8
cM proximal to Drh1a. However, we excluded MGMT
from the candidate genes because the mRNA level in
F2 was not correlated with other preneoplastic
lesion parameters (Table 1)
, and the peak of Drh1a was
evidently discrete from that of MGMT.
The linkage peak for Drh1b was about 15 cM distal from that of Drh1a, where percentage area, GST-P mRNA, and the number of EAF showed significant linkage. Aldh1 and Anx1 were shown to be localized at this position in a recent RH mapping study (34) . Drh1c showed a small peak at the telomeric end of RNO1, which was suggested to be correlated with the size of foci. Cyp2C and Cyp17 are possible candidate genes. These cytochrome P450 enzymes may affect the susceptibility to cancer through metabolic activation of carcinogens.
Two QTL, Drh2a and Drh2b, were mapped to the
distal segment of RNO4. One of the candidate genes for Drh2a
is growth hormone-releasing hormone receptor (Ghrhr). The
little mice (35)
, which are defective in
Ghrhr, develop fewer liver cancers than their wild-type
counterparts. The body weight of DRH strain rats is consistently larger
than that of F344 rats. Interestingly, interval mapping using body
weight before 3'-Me-DAB administration showed a low peak of QTL with a
lod score of 2.4 at Dhr2a (data not shown). Polymorphism at
Ghrhr may affect the number and progression of liver
preneoplastic lesions. At Drh2b, Tgf
may be a
possible candidate gene. Tgf is a ligand of the epidermal growth
factor receptor and stimulates the growth of liver cells in an
autocrine loop (1
, 36)
.
De Miglio et al. (10) recently reported genetic resistance of BN rats to chemically induced HCC in (BN x F344) x F344 rats. The QTL on RNO7 and RNO10 are significantly associated with tumor volume fraction, and the presence of other QTL is also suggested on RNO4 and RNO8. The BN quantitative trait locus on RNO7 is a susceptibility locus, and the QTL on RNO10, RNO4, and RNO8 are resistance loci. The observation that these QTL affect tumor size but not the number of tumors may suggest that they modify the growth of transformed hepatocytes, but not the frequency of malignant transformation. Effects are also seen on volume but not on the number of EAF (10) . No LOH at these loci is observed in HCCs developed in resistant (BN x F344)F1 hybrid rats (37) . Judging from the chromosomal locations of these loci, DRH resistance seemed distinct from that of BN rats. However, in the study by De Miglio et al. (10) , the recessive resistance locus on RNO1 might have been overlooked because they examined backcrosses to susceptible F344 rats rather than F2 rats.
Genetic predisposition to HCC in mice has been studied extensively by two groups. Drinkwater et al. (38) identified a susceptibility gene in C3H mice in a cross between C3H and C57BL and later mapped the gene on MMU1 (39) . Gariboldi et al. (40) and Manenti et al. (41) identified six susceptibility loci for urethane-induced liver cancers: (a) Hcs1 (MMU7); (b) Hcs2 (MMU8); (c) Hcs3 (MMU12); (d) Hcs4 (MMU2); (e) Hcs5 (MMU5); and (f) Hcs6 (MMU19). Using N,N-diethylnitrosamine, Lee et al. (42) and Poole and Drinkwater (43) mapped resistance genes to HCCs to Hcr1 (MMU4) and Hcr2 (MMU10). Of these, Hcs1 was on RNO1 but was more centromeric than the Drh1 cluster. Hcs5 was on RNO4 but was also more centromeric than the Drh2 cluster. Hcs6 was on MMU 19 and was on the telomeric portion of RNO1. Its map position suggested that it might be homologous to either Drh1b or Drh1c. In humans, there have been reports of familial clusters of HCC (44, 45, 46) . Polymorphisms in drug-metabolizing enzyme genes have been shown to be correlated to genetic risk of HCC in humans (47) . To explore putative tumor suppressor genes of HCC, LOH has been studied extensively in human HCC (48, 49, 50, 51, 52, 53) and also in rodent models (37 , 54) . The telomeric segment of RNO1 is homologous to 11p15, 11q13, 9p21, and 10q23–26, and the telomeric segment of RNO4 is homologous to 3p, 12p12, 10q11.2, 3p25, and 12p13.2-p11.2. Frequent LOH in these segment has not been reported in human HCC, except for 11p15 in hepatoblastomas (55) . The difference in species and agent of induction may be responsible for these discrepancies.
Genetic resistance of DRH strain rats was more complicated than we had first assumed. Combination of recessive and semidominant QTL could explain a large proportion of the phenotypic variance between DRH and F344 rats. However, there were some ambiguities in the number of independent QTL even with the composite interval mapping analysis. To clarify these problems, a far larger set of genetic analysis is required. Furthermore, it remains unclear whether such resistance has been acquired by mutational events in the germ line or by long-term selection. There are several promising candidate genes for these QTL. This study provided useful information for the analysis of genetic predisposition to chemically induced HCC.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported by a grant-in-aid from the Ministry of
Education, Culture, Sports and Science, Japan and a grant for cancer
research from the Ministry of Health and Welfare, Japan. 
2 To whom requests for reprints should be
addressed, at Department of Pathology and Biology of Diseases, Kyoto
University Graduate School of Medicine, Yoshida-Konoe-cho, Sakyo-ku,
Kyoto 606-8501, Japan. Phone: 81-75-753-4421; Fax: 81-75-753-4432;
E-mail: hiai{at}path1.med.kyoto-u.ac.jp
3 The abbreviations used are: GST-P, glutathione
S-transferase placental form; 3'-Me-DAB,
3'-methyl-4-dimethylaminoazobenzene; GGT, -glutamyltransferase; QTL,
quantitative trait loci; EAF, enzyme-altered foci; HCC, hepatocellular
carcinoma; MGMT, O6-methylguanine DNA
methyltransferase; M6P/IGF2R, mannose 6-phosphatase/insulin-like growth
factor 2 receptor; lod, logarithm of odds; RNO, rat chromosome; MMU,
mouse chromosome; BN, Brown Norway; DAB, 3,3'-diaminobenzidine; LOH,
loss of heterozygosity.
4 http://waldo.wi.mit.edu/rat/public/images/csomes/
(November 22, 1998).
Received 10/27/99. Accepted 4/ 3/00.
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-glutamyl transpeptidase positive lesions induced by initiation-promotion in ornithine carbamyltransferase mosaic mice. Jpn. J. Cancer Res., 79: 148-151, 1988.[Medline]
-glutamyltransferase activity by 3'-methyl-4-dimethylaminoazobenzene in the liver of rats given carcinogen-containing diet for several generations. Jpn. J. Cancer Res., 77: 139-144, 1986.[Medline]
-glutamyltranspeptidase during N-nitrosobis(2-hydroxypropyl)amine-induced lung carcinogenesis in rats. Carcinogenesis (Lond.), 9: 339-404, 1988.
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