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PubMed1981

Urinary excretion of dimethylnitrosamine: a quantitative relationship between dose and urinary excretion.

The urinary excretion of dimethylnitrosamine (DMN) was studied in male Sprague-Dawley rats. Animals were given DMN (3, 5, 10, 20, 30 and 50 mg/kg body weight, i.p.) or [3H]DMN (0.1, 1 and 3 mg; 8.7, 1.5 and 0.28 mCi/kg body weight, respectively, i.p.) diluted with sterile 0.9% NaCl. Urine was collected for 24 h after dosing. DMN was quantitated by gas chromatography using a Thermal Energy Analyzer as detector and [3H]DMN by liquid scintillation counting after purification by high pressure liquid chromatography. Multiple regression analysis programs were used to evaluate the fit of the data to a variety of models relating excretion to dose. All models which gave an acceptable fit including a term for dose squared. The models are discussed in terms of the relationship between urinary excretion and blood clearance of DMN.

Animals↗
PubMed1981

Effects of chloroform and dimethylnitrosamine on renal carcinogenesis in unilaterally nephrectomized rats fed formic acid 2-[4-(5-nitro-2-furyl)-2-thiazolyl]hydrazide.

Factors enhancing renal carcinogenesis induced by formic acid 2-[4-(5-nitro-2-furyl)-2-thiazolyl] hydrazide (FNT) were studied. Five groups of rats were used. Groups 1 and 2 were subjected to right nephrectomy and 2 days late they were injected with 20 mg/kg body weight of dimethylnitrosamine (DMN). From one week after nephrectomy, group 1 was fed on 0.2% FNT diet continuously to the end of the experiment, and group 2 was given normal diet. In week 2, they were given 400 mg/kg body weight of chloroform (CHCl3) orally. Groups 3 and 4 were given ChCl3 first and 2 days later injected with DMN. Group 3 was then fed FNT diet and group 4 was fed basal diet continuously. In week 2, groups 3 and 4 were subjected to unilateral nephrectomy. Group 5 was given FNT diet without other treatment. The incidences of tubular hyperplasia in groups 1, 3 and 5 were 53.3%, 52.9%, and 0%, respectively, at week 16 and 100%, 94.9% and 94.1%, respectively, at week 32. Moreover, the incidences of renal cell tumors in these groups were 85.0%, 88.9% and 17.6%, respectively, at week 32. Thus, the inductions of tubular hyperplasia and renal cell tumor were markedly enhanced by combined treatment with CHCl3, DMN, unilateral nephrectomy and FNT in the initiating and promoting stages.

Animals↗
PubMed1981

Effect of pretreatment with pregnenolone-16 alpha-carbonitrile and protein-free diet on the metabolism and carcinogenicity of dimethylnitrosamine.

Pretreatment with protein-free diet (PFD) or pregnenolone-16 alpha-carbonitrile (PCN) markedly reduces th toxicity of dimethylnitrosamine (DMN) in rats. PFD causes a shift in DMN metabolism form liver to kidney with a consequent increase in the incidence of kidney tumours. The present study was designed to evaluate the effect of PCN on the carcinogenicity and metabolism of DMN. After pretreatment with PFD, PCN or a combination of both, adult female Wistar rats received a single i.p. dose (60 mg/kg) of DMN. Animals pretreated with PFD and PFD + PCN developed a similar incidence of kidney tumours (83-85%) after a mean survival time of 357 and 396 days, respectively, Animals pretreated with PCN alone had a 50% incidence of renal tumours after a mean survival time of 672 days. This correlates with the initial extent of DMN-induced methylation of kidney DNA. Concentrations of 7-methylguanine and O6-methylguanine were highest and very similar in PFD- and PFD + PCN-pretreated rats, whereas in PCN-conditioned animals the extent of base methylation was 38% lower. Extrarenal tumours, in particular large cystic cholangiomas of the liver, were most frequent in PCN-pretreated rats, probably due to their longer survival time. In contrast to animals pretreated with either PCN or PFD, hepatic DNA methylation was markedly reduced (54-60%) in animals pretreated with both PFD and PCN.

Animals↗
PubMed1983

Inhibitory effects of carbon tetrachloride on dimethylnitrosamine metabolism and DNA alkylation.

The effect of CCl4 pretreatment (dose range from 0.5 to 2.0 ml/kg body weight) on the pathways of dimethylnitrosamine (DMN) metabolism was investigated. The oxidative-N-demethylation by the enzymes, DMN-demethylase I and II operating at low (4 mM) and high (200 mM) substrate concentration, respectively, was greatly reduced in a dose-dependent manner. In addition, the generation of an electrophilic intermediate capable of methylating DNA, specifically at the N-7 and O-6 positions of guanine, was completely inhibited by CCl4 (0.5 ml/kg body weight) pretreatment. When indole feeding (1% in the diet for 8 days prior to CCl4 administration) was employed as a means to enhance DMN-demethylase activities, it was found that the reduction of DMN-demethylase activities was more pronounced in these rats than in the controls. In agreement with earlier findings, 7-methylguanine and O6-methylguanine were not detectable in the CCl4 pretreated group. These results suggest that CCl4 exerts a strong inhibitory action on hepatic DMN metabolism, in particular on the pathway leading to alkylation of DNA guanine. This phenomenon may explain the protective role of CCl4 against DMN-induced hepatotoxicity and perhaps, carcinogenicity, believed to be closely associated with the abnormal modifications of DNA.

Alkylation↗
PubMed1983

Enhancement by testosterone of dimethylnitrosamine carcinogenesis in lung, liver and kidney of inbred NZR/Gd female rats.

The effect of androgenic treatments on single dose dimethylnitrosamine (DMN) carcinogenesis was studied in 60 female NZR/Gd inbred rats, 25 of which were intact and received DMN 20 mg/kg i.p. in one dose after 48 h starvation, while 35 received DMN combined with testosterone injections every 4 weeks beginning 15 days before or after DMN, and in 29 rats combined also with ovariectomy. Sixteen female rats underwent ovariectomy and received testosterone every 4 weeks with no DMN. There were also 107 untreated intact contemporaneous control female rats. A single dose of DMN induced alveologenic lung (16%), hepatocellular (24%) and kidney epithelial (44%) tumours in intact rats, and the incidences of lethal tumours at these sites were significantly enhanced by androgenic treatments following the carcinogen, most markedly in the kidney. Androgenic treatment given before DMN injection had no significant effect on kidney or liver tumour incidences, but the carcinogenic response in lung was still strongly enhanced.

Animals↗
PubMed1984

Ethanol and dimethylnitrosamine and diethylnitrosamine metabolism and disposition in the rat. Possible relevance to the influence of ethanol on human cancer incidence.

Alcohol consumption is associated with an increase in human cancer, notably of the oesophagus. We have found that ethanol will alter profoundly the distribution of two carcinogenic nitrosamines in the rat. Small oral doses of dimethylnitrosamine (NDMA) are absorbed from the portal blood as it passes through the liver, and do not reach the extrahepatic organs. Ethanol, equivalent to a man drinking 1 pint (0.5 l) of beer, prevents this first pass clearance in the rat and exposes sensitive extrahepatic organs to this carcinogen. As a consequence the alkylation of kidney DNA by 35 micrograms NDMA/kg body weight was increased 4.6-fold by concurrent administration of 240 mg ethanol/kg, and smaller doses of [14C]-NDMA produced detectable alkylation of kidney DNA only if the rats were given ethanol. Measurement of metabolism of NDMA by liver slices confirmed that this action of ethanol is the result of inhibition by ethanol of NDMA metabolism in liver (Ki = 0.5 mM). Comparison of urinary excretion in man and rat suggests that ethanol also inhibits first pass clearance of NDMA in man. There was no complete first pass clearance of diethylnitrosamine (NDEA), but while ethylation of kidney DNA was decreased by ethanol, that of oesophageal DNA was increased between 1.8- and 4.6-fold. Measurement of the metabolism of NDEA to CO2 by liver slices, kidney slices, and oesophageal epithelium suggest that the changes in alkylation of kidney and oesophageal DNA are the result of selective inhibition of NDEA metabolism in liver and kidney. The ethylation of oesophageal DNA was greater relative to liver after a small dose than after a large dose possibly because of the low Km of the oesophageal metabolic activating system relative to that in liver and kidney. These results explain experiments showing that concurrent administration of ethanol increases the carcinogenicity and alters the organs affected by these nitrosamines. It is tentatively proposed that the effect of ethanol on human cancer incidence is mediated through similar influences on the metabolism and disposition of the nitrosamines to which man is exposed.

Alkylation↗
PubMed1984

Null effects of vitamin A analogs on the dimethylnitrosamine kidney tumor model.

The effect of retinoids on the induction of both epithelial and mesenchymal tumors of the rat kidney by a single dose of 40 mg/kg dimethylnitrosamine was tested using 13-cis-retinoic acid and the trimethylmethoxy phenyl analog of retinoic acid ethylamide. 13-cis-retinoic acid was administered for 3 weeks, 10 weeks, or 26 weeks, post-carcinogen treatment, in order to coincide with known morphological phases occurring within the kidney which culminated in the development of macroscopic tumors. The ethylamide analog and placebo beadlets were administered for the 26 week period only. None of the retinoid schedules significantly influenced the survival of the animals, nor the incidences of renal mesenchymal tumors or renal cell adenomas/adenocarcinomas. Tumor latency, histological grade or frequency of metastatic invasion were also unaltered by the treatments. Possible reasons for the observed lack of effect are discussed, including speculation regarding the potency of this single-dose model of chemical carcinogenesis.

Animals↗
PubMed1984

The effects of estrogen on single dose dimethylnitrosamine carcinogenesis in male inbred Crl/CDF rats.

The effect of longterm estrogen treatment (estradiol valerate) on male rats injected i.p. once with dimethylnitrosamine (DMN, 30 mg/kg, with protein starvation), was studied in 167 male inbred Crl/CDF rats. DMN was given at 40 days (immature rats) or at 90 days (mature rats) to investigate the action of carcinogen and hormone at different stages of development. Estrogen reduced life expectancy of male animals, and was associated with greatly increased breast tumour incidence (to 30%) compared with controls (3%, p less than 0.01). DMN alone enhanced lung tumorigenesis (p less than 0.001) and chronic estrogen treatment significantly reduced both the incidence and multiplicity of DMN-induced lung tumours in male rats (p less than 0.001). Also, estrogen treatment lowered the incidence of spontaneous lung tumours (p less than 0.005). The higher incidence of animals with kidney tubular adenomas and carcinomas induced by DMN in both mature and immature rats was statistically significant (p less than 0.001), but estrogen and the age at carcinogen treatment had no effect. Lethal mesenchymal kidney tumours developed in immature rats exposed to DMN (p less than 0.001), but only developed in mature DMN-treated rats if they received estrogen as well.

Adenoma↗
PubMed1984

High frequency, single-dose model of renal adenoma/carcinoma induction using dimethylnitrosamine in Crl:(W)BR rats.

Following discovery that the type of kidney neoplasm induced in protein-deprived Wistar rats by a single dose of dimethylnitrosamine (DMN) was age-dependent, this study aimed to refine the system in order to develop a high frequency model for the induction of cortical epithelial tumors with low mesenchymal tumor incidence. Using outbred female Crl:(W)BR (Charles River Wistar) rats, DMN at a dose of 30 mg/kg was administered at 9-10 weeks of age following a 5-day period of high-carbohydrate/no-protein diet. From a total of 49 rats, 43 survived the early toxicity and 91% of these developed renal tumors. Mesenchymal tumors were present in only 9% of the tumor-bearing animals. In contrast, 70% of the rats developed epithelial tumors of the tubules classifiable on a size and histological basis as adenocarcinomas/carcinomas in response to DMN. A further 21% of rats had smaller proliferative lesions designated as adenomas, making the total cortical epithelial tumor incidence in excess of 90%. The malignant potential of the epithelial tumors was underscored by the presence of metastatic invasion, mainly involving the lungs, in 15% of the tumor-bearing rats. Metastatic behavior correlated with progressive growth of the carcinomas over a period of time exceeding 1.5 years to dimensions usually exceeding 2.9 cm diameter. Of the tumors approaching or exceeding this size, the metastatic rate was almost 50%. Thus, the administration of DMN to 65-70 days old, protein-deprived Wistar rats provides a potent, single dose model for the study of renal epithelial carcinogenesis with insignificant mesenchymal tumor induction and without the continuing toxicity which perturbs regimens based on repeated or continuous exposures.

Adenoma↗
PubMed1985

Differential renal tumor response to N-ethylnitrosourea and dimethylnitrosamine in the Nb rat: basis for a new rodent model of nephroblastoma.

Previous studies have indicated that the Nb rat has a higher predisposition to the spontaneous development of nephroblastoma than most other strains of laboratory rat. In order to determine whether this inherent susceptibility could be exploited as a model for Wilms' tumor, Nb rats were treated with various chemicals in regimens known to be associated with renal tumor induction in the young rat. Nb rats were either exposed in utero to various dose levels of N-ethylnitrosourea (ENU) on day 18 +/- 1 of gestation, injected s.c. with one 25 mg/kg dose of dimethylnitrosamine (DMN) as neonates or dosed twice orally with 7,12-dimethylbenz[a]anthracene (DMBA) shortly after ovariectomy. Transplancental ENU at a dose of 60 mg/kg resulted in an average of 50% frequency of unequivocal nephroblastomas in both sexes with no renal mesenchymal tumors. In contrast, DMN administered to neonates produced a similar incidence of renal mesenchymal tumors but no nephroblastomas. DMBA in the ovariectomized female was not a successful strategy for inducing primary renal tumors in the Nb rat (0 nephroblastomas, 1 renal mesenchymal tumor in 16 effective survivors), although the kidney was sometimes the site for metastatic invasion by tumors originating at other locations. The induction of nephroblastomas and renal mesenchymal tumors by ENU and DMN in parallel experiments emphasized the many differences which establish them as distinct and unrelated tumor entities. The relatively high incidence of nephroblastoma in the Nb rat using transplacentally administered ENU appears to represent a suitable basis for developing a rodent model of human nephroblastoma or Wilms' tumor.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1985

Genotoxicity of dimethylnitrosamine in the presence of chrysotile asbestos UICC B and xonotlite.

Interactions of particulates with chemical genotoxic agents may play an important role in the induction of carcinogenesis. With respect to bronchogenic cancer, the synergism associated with combined exposure to asbestos and tobacco smoke is a well-documented phenomenon. The present work focused on chrysotile asbestos and xonotlite. The latter is a fibrous calcium silicate which is increasingly being used to replace asbestos in various industrial applications. The study was aimed at testing the possible interaction of these materials with dimethylnitrosamine (DMN), a genotoxic component of tobacco smoke. The capacity of fibers to interfere with the genotoxic response elicited by DMN in the UDS/hepatocyte assay system specifically designed for sensitive detection of short-patch DNA repair, was looked for. The properties of the selected fibers with respect to binding affinity towards DMN were also examined.

2-Acetylaminofluorene↗
PubMed1986

Formation and stability of alkylated pyrimidines and purines (including imidazole ring-opened 7-alkylguanine) and alkylphosphotriesters in liver DNA of adult rats treated with ethylnitrosourea or dimethylnitrosamine.

Adult rats received a single injection of the carcinogens N-ethyl-N-nitrosourea (ENU) or N,N-dimethylnitrosamine (DMN) and were killed after various time intervals (up to 56 days). Liver DNA was analysed by h.p.l.c. for alkylated purines [3-alkyladenine (3-alkylAde), 7-alkylAde, 3-alkylguanine (3-alkylGua), O6-alkylGua, 7-alkylGua, imidazole ring-opened (ro) 7-alkylGua] and alkylated pyrimidines [O2-alkylcytosine (O2-alkylCyt), 3-alkylCyt, O2-alkylthymine (O2-alkylThy), 3-alkylThy, O4-alkylThy]. Alkylphosphotriesters were assayed by both h.p.l.c. [alkylphosphotriester of thymidyl(3'-5')thymidine, (dTp(alkyl)dT)] and alkaline sucrose sedimentation (total phosphotriesters). No significant amounts of 3-alkylCyt and ro 7-alkylGua were observed, but the presence of all other products could be established 2 h after DMN or ENU. At that moment the relative amounts of some products (O2-alkylCyt, O2-alkylThy, O4-alkylThy, O6-alkylGua), when compared with 7-alkylGua, were smaller than those observed after in vitro alkylation of isolated DNA. This suggests either a lower accessibility of some sites in DNA in situ, or (as known already for O6-alkylGua) the presence of rapidly exhausted, fast repair modes for these adducts. The in vivo stability of ethylated products was (much) higher than that of the homologous methylated products. In the case of O-alkylated thymidines this difference was impressive: apparent half-life values of 17 days for O2-ethylthymine (O2-EtThy) and 14 days for O4-EtThy were calculated, whereas the corresponding values for O2-methylthymine (O2-MeThy) and O4-MeThy were 12 h and less than 4 h, respectively. Substantial, although smaller differences were also found for O2-alkylCyt (86 versus less than 4 h), 3-alkylGua (104 versus 17 h) and dTp(alkyl)dT (32 versus 7 days), whereas the rates of removal of 7-EtGua and 7-MeGua differed by 2.5-5 times (depending on the period compared). At 56 days after ENU the two major lesions were the ethylphosphotriester and O2-EtThy, whereas only traces of 7-EtGua were observed. Parenchymal and non-parenchymal liver cells of some DMN-treated rats were separated before DNA isolation. It was found that the extents of DNA alkylation at 6 h after DMN administration were almost identical, indicating that DMN activation is the same for both cell types. The results are discussed in relation to the carcinogenic effects of methylating and ethylating agents.

Alkylation↗
PubMed1986

Protection of crocin dyes on the acute hepatic damage induced by aflatoxin B1 and dimethylnitrosamine in rats.

Chemopreventive agents are compounds that inhibit carcinogenesis when administered prior or subsequent to a course of carcinogen administration. The effects of dietary administration of crocin dyes on the hepatic damage induced by aflatoxin B1 (AFB1) and dimethylnitrosamine (DMN) in rats were investigated. Female Sprague-Dawley rats were treated with different dosages of AFB1 (0.9 or 4.5 mg/kg) or DMN (8 or 20 mg/kg) by i.p. administration, and the different degrees of hepatic damage were revealed by the elevations of levels of serum marker enzymes such as aspartate amino-transferase, alanine aminotransferase, alkaline phosphatase, gamma-glutamyl transpeptidase and lactic dehydrogenase. Pre-treatment of the animals with crocin dyes 50 mg/kg daily for three consecutive days, the enzyme elevations were significantly suppressed. This suggested that the crocin dyes possessed chemopreventive effects on the early acute hepatic damage induced by AFB1 or DMN. Feeding experiments demonstrated that crocin dyes at 0.1% in the diet could suppress partially the chronic hepatic damage induced by multiple dosages of AFB1 or DMN, but at a higher concentration of 1% crocin dye failed to do so because of their host toxicity. Crocin dyes are extracted from the fruits of Gardenia jasminoides and consist of carotenoids and geniposides as active principles. The protective mechanisms of crocin dyes may be attributed to their carotenoids which are converted metabolically to retinoids in rats.

Aflatoxin B1↗
PubMed1986

Persistence of preclastogenic damage in hepatocytes of rats exposed to ethylnitrosourea, diethylnitrosamine, dimethylnitrosamine and methyl methanesulphonate. Correlation with DNA O-alkylation.

Male Wistar rats received a single injection of ethylnitrosourea (ENU; 140 mg/kg), dimethylnitrosamine (DMN; 10 mg/kg) or methyl methanesulphonate (MMS; 80 mg/kg). After 1, 6, 28 and 56 days liver cells were assayed for the presence of preclastogenic lesions. This was done by analysis of micronuclei in hepatocytes isolated at 2, 3 and 4 days after partial hepatectomy. Treatment with MMS did not give rise to a statistically significant increased micronucleus frequency after the two time intervals tested (1 and 6 days). In contrast, frequencies of micronuclei were significantly enhanced at all time intervals after treatment with either ENU or DMN. These results support our previous conclusion that only those alkylating agents which give rise to substantial DNA O-alkylation are able to induce long-lived preclastogenic damage in rat liver cells. Both after ENU and DMN treatment, frequencies of micronuclei were significantly higher at day 6 than at days 1, 28 and 56. It is postulated that part of the primary preclastogenic lesions (supposed to be DNA adducts) are converted into secondary preclastogenic lesions during the first period after exposure to the chemicals. Apparently, both primary and secondary preclastogenic lesions are gradually lost after day 6. This loss is rather low (less than 25%) after ENU, but more impressive after DMN (approximately 60%). The persistent nature of preclastogenic damage induced by diethylnitrosamine was demonstrated in an experiment which showed that a single dose of this agent (50 mg/kg) had the same clastogenic effect as a fractionated dose (five weekly injections of 10 mg/kg). This result also implies that a threshold dose for induction of micronuclei, if present, must be very low, appreciably below 10 mg/kg.

Alkylation↗
PubMed1987

Visualization of O6-methylguanine in target cell nuclei of dimethylnitrosamine-treated human pancreas by a murine monoclonal antibody.

A murine monoclonal IgG2b with high affinity and specificity for O6-methylguanine was developed. This allowed visualization of this adduct in paraffin-embedded sections by indirect fluorescence or immunoperoxidase methods. The antibody was used to study and compare the formation and persistence of this adduct detected by immunohistochemistry and the presence of 14C methyl by autoradiography in sections from adult human pancreas explants exposed to [14C methyl]dimethylnitrosamine (DMN) and organ-cultured for up to 7 days. O6-methylguanine was detectable randomly and with varied intensity in parenchymal cell nuclei and cytoplasms, 6 h after exposure to DMN. Following RNase treatment, however, only 7.5% of nuclei revealed measurable staining. The positive nuclei decreased to 2.5% within 24 h and remained about the same throughout the 7 days of culture. This correlated well with the change in percentage of positive nuclei for 14C methyl autoradiographic grains which were selectively condensed over the O6-methylguanine-stained nuclei. The data demonstrate a subpopulation of repair-deficient parenchymal cells of human pancreas exposed to DMN.

Animals↗
PubMed1987

Enhancement of dimethylnitrosamine-initiated hepatocarcinogenesis in hamsters by subsequent administration of carbon tetrachloride but not phenobarbital or p,p'-dichlorodiphenyltrichloroethane.

The effect of phenobarbital (PB), p,p'-dichlorodiphenyltrichloroethane (DDT) or carbon tetrachloride (CCl4) on dimethylnitrosamine (DMN)-induced hepatocarcinogenesis in Syrian golden hamsters was examined. Hamsters were given a single injection of DMN (6 mg/kg body wt) followed by either PB or DDT in the diet or repeated CCl4 gavage for 30 weeks. The numbers of both altered liver cell foci and hepatocellular neoplasms in the hamsters given 0.1 ml CCl4, i.g. once every 2 weeks after the DMN were significantly higher than in the animals given DMN alone. PB or DDT (500 p.p.m. in the diet) after DMN did not produce a significantly higher incidence of altered foci or hepatocellular neoplasms compared to DMN alone. Thus, an enhancing effect of CCl4 on DMN-induced hepatocarcinogenesis in the hamster was demonstrated, but neither PB or DDT--both liver neoplasm promoters in rats and mice--displayed promoting activity under the conditions of study.

Animals↗
PubMed1975

In vitro culture of cells isolate from dimethylnitrosamine-induced renal mesenchymal tumors of the rat. I. Qualitative morphology.

The in vitro morphology of cells isolated from renal mesenchymal tumors induced in rats by a single ip injection of dimethylnitrosamine was followed in short- and long-term culture. The morphology of cells isolated from normal rat-kidney cortex was studied for comparison. Primary tumor-cell isolates consisted of a range of mesenchymal cell forms interspersed between discrete, homogeneous islands of cohesive epithelium-like cells. The latter were presumably derived from renal parenchyma that had been engulfed within the in vivo neoplasm by proliferating tumor cells, since this epithelial component did not survive serial subculture. Established tumor cell lines consisted of a pleomorphic range of mesenchymal forms resembling the descriptions of various cell types in vitro, including fibroblasts, smooth muscle cells, and endothelial cells. A range of mesenchymal cell forms in culture therefore correlated with the heterogeneous histologic nature of the in vivo neoplasm in which fibroblasts, smooth muscle fibers, and endothelium-like cells were also represented. Multinucleate or polymorphonuclear giant cells were characteristic of tumor cell cultures, whereas large, expanded polygonal cells with longitudinal striations were characteristic of normal kidney cell cultures. Some tumor cell cultures were typified by cells with cytoplasmic vacuolation and some by the acquisition of an epithelioid form at high cell density, a change not preceded by islands of cohesive, epithelium-like cells at preconfluent stages.

Animals↗
PubMed1975

Metabolism of dimethylnitrosamine to mutagenic intermediates by kidney microsomal enzymes and correlation with reported host susceptibility to kidney tumors.

Purified kidney microsomal enzymes from C3H/HeJ and Ha/1CR mice exhibited an unusually high capacity to generate mutagenic metabolites from dimethylnitrosamine (DMNA) when compared with similar enzyme preparations from BALB/cJ and RF/J mice. These results suggested that the DMNA-activating enzymes involved in mutagen formation were either present at higher levels or were more active in the kidneys of C3H/HeJ and Ha/ICR mice than in those of the other two strains. This strain difference correlated with the established susceptibility of these four strains to the neoplastic activity of DMNA.

Animals↗