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PubMed2005

Promotion of thyroid carcinogenesis by para-aminobenzoic acid in rats initiated with N-bis(2-hydroxypropyl)nitrosamine.

Sulfonamide analogues of para-aminobenzoic acid (PABA), a precursor of folate synthesis, have beneficial effects as antifolate, but thyroid peroxidase inhibition has been reported as a side effect that results in promotion of rat thyroid carcinogenesis. In the present study, effects of PABA itself on F344 rat thyroid carcinogenesis after initiation with N-bis(2-hydroxypropyl)nitrosamine (DHPN) were evaluated. In experiment 1, rats in groups 1-4 received a single subcutaneous injection of DHPN at 2800 mg/kg, and groups 5 and 6 received vehicle saline alone. From 1 week after DHPN initiation, rats in groups 2, 3, 4, and 6 were fed basal diet containing 0.25%, 0.5%, 1.0%, and 1.0% PABA, respectively, for 40 weeks. Rats in groups 1 and 5 received basal diet alone throughout the experiment. The final incidence of thyroid follicular cell adenomas and adenocarcinomas was significantly (p < 0.05 or 0.01) increased in groups 3 and 4 as compared to group 1. No thyroid tumors were found in groups 5 and 6. In experiment 2, animals in group 1 were fed basal diet alone, while groups 2 and 3 were given 0.5% and 1.0% PABA in the diet, respectively, for 2 weeks. Thyroid weights in group 3, and serum thyroid stimulating hormone level and proliferative activity of follicular cells in groups 2 and 3 were significantly (p < 0.05 or 0.01) elevated. In addition, the serum thyroxine level in group 3 was significantly (p < 0.05) depressed. These results clearly indicate that PABA exerts promotion/progression effects on rat thyroid carcinogenesis as a result of hypothyroidism followed by negative-feedback via the thyroid-pituitary axis.

4-Aminobenzoic Acid↗
PubMed2005

Pronounced synergistic promotion of N-bis(2-hydroxypropyl)nitrosamine-initiated thyroid tumorigenesis in rats treated with excess soybean and iodine-deficient diets.

We have reported that excess soybean treatment and iodine deficiency synergistically interact, resulting in remarkable induction of thyroid hyperplasias in rats. In the present study, modifying effects of excess soybean and iodine-deficient diets were investigated in the post-initiation phase of N-bis(2-hydroxypropyl)nitrosamine [DHPN]-initiated thyroid tumorigenesis in rats. AIN-93G in which casein was replaced with gluten was used as a basal diet to avoid possible iodine contamination. In Experiment 1, F-344 rats of both sexes were sc injected with DHPN at a dose of 2800 mg/kg body weight and then fed a diet containing 0%, 0.8%, 4%, or 20% defatted soybean for 12 weeks, with proportional replacement of gluten by soybean flour. Although no thyroid proliferative lesions were found in any group, the absolute thyroid weights were significantly (p < 0.01) elevated with the 20% soybean treatment. In Experiment 2, after similar sc injection of DHPN, rats were fed a basal diet or a diet containing 20% soybean under iodine normal or deficient conditions for 12 weeks. Soybean feeding to both sexes under iodine deficient but not normal conditions dramatically enhanced the development of thyroid follicular adenomas (p < 0.01) and adenocarcinomas (p < 0.05), in good agreement with decrease in thyroxine and increase in thyroid-stimulating hormone. Thus co-exposure to excess soybean and iodine deficiency results in synergistic promotion of DHPN-initiated thyroid tumorigenesis in rats, of which mechanisms appear to primarily involve effects on serum hormone levels.

Adenocarcinoma↗
PubMed1987

Pancreatic tumor antigen in transplantable adenocarcinomas induced by N-bis(2-hydroxypropyl)nitrosamine in hamsters.

An attempt was made to detect a pancreatic tumor antigen (PTA) in transplantable pancreatic adenocarcinomas induced by N-bis(2-hydroxypropyl)nitrosamine (DHPN) in hamsters. Antibody against antigenic protein was raised by immunizing rabbits with whole homogenate of the tumors transplanted into the back of hamsters. PTA was purified by affinity chromatography and shown to have the physicochemical properties of a glycoprotein with a molecular weight of 800,000, migrating in the beta regions upon agarose gel electrophoresis. Loss of immunological properties was observed after heating at 65 degrees C for 30 min. Enzyme immunoassay revealed that the levels of PTA in the serum and tissue showed a positive correlation with the induction of the presence of tumor, and size of the tumor. It is tentatively suggested that PTA values above 150 ng/ml serum are indicators of tumors, because in normal hamsters the PTA range is from 25 to 130 ng/ml serum. Immunohistochemically, PTA was demonstrated to be localized within the cytoplasm of epithelial tumor cells of well-differentiated tubular adenocarcinomas.

Adenocarcinoma↗
PubMed2005

The L84F and the I143V polymorphisms in the O6-methylguanine-DNA-methyltransferase (MGMT) gene increase human sensitivity to the genotoxic effects of the tobacco-specific nitrosamine carcinogen NNK.

O-Methylguanine-DNA-methyltransferase (MGMT) is a direct-reversal DNA repair protein that removes DNA adducts formed by alkylating mutagens found in tobacco smoke. Several coding single nucleotide polymorphisms (cSNPs) in the MGMT gene have been reported. However, their effect on the levels and types of genetic damage induced by specific environmental carcinogens remains to be fully elucidated. We developed two novel genotyping techniques and used them, in conjunction with the mutagen-sensitivity assay, to test the hypothesis that the L84F and I143V cSNPs in the MGMT gene confer increased sensitivity to genetic damage induced by the alkylating tobacco-specific nitrosamine carcinogen NNK. Lymphocytes from 114 healthy volunteers were exposed in vitro to NNK, and the genotoxic response was assessed by measuring chromosome aberration (CA) frequencies. A significant (P<0.02) increase in NNK-induced CA was observed in cells from individuals with the 84F polymorphism compared to cells from individuals homozygous for the referent L84 allele. A significant positive interaction between this cSNP and smoking, gender and age was observed (P<0.03). In subjects with the variant 143V allele, significantly higher levels of NNK-induced CA were observed in males and in young subjects (<43 years old) compared to subjects homozygous for the referent I143 allele (P<0.02). Individuals who inherited two cSNPs had significantly higher levels of NNK-induced CA compared to individuals with none or with one cSNP (P<0.002). These new data suggest that the 84F and 143V cSNPs may alter the function characteristics of the MGMT protein, resulting in suboptimal repair of genetic damage induced by NNK.

Adult↗
PubMed1988

The induction of bladder tumors in F344 rats by intravesicular administration of some nitrosamines.

Three nitrosamines, metabolically related and formed in vivo from the bladder carcinogen nitrosomethyl-n-octylamine, were administered to groups of 12 female F344 rats by intraurethral instillation twice a week for 30 weeks. All three compounds induced tumors in the urinary bladder. Nitrosomethyl-2-oxopropylamine at 10 mg/ml was the most potent, causing death of half of the animals with tumors at 43 weeks, following a total dose of 1.0 mmol; most of the rats also had tumors of the nasal mucosa, and there were some tumors of the kidney and kidney pelvis. Nitrosomethyl-2-hydroxypropylamine at 10 mg/ml (total dose 1.0 mmol) was much less effective, the median week of death being 83 weeks. In addition to bladder tumors, this group had tumors of the nasal mucosa, esophagus, and kidney. Nitrosomethyl-3-carboxypropylamine at 75 mg/ml and a total dose of 6.2 mmol per rat induced a high incidence of bladder tumors and tumors of the kidney pelvis, but not tumors of the nasal mucosa; the median week of death for this group was 55 weeks. It is concluded that nitrosomethyl-n-alkylamines that induce bladder tumors by oral administration to rats are metabolized to nitrosomethyl-3-carboxypropylamine, which is excreted in the urine and further metabolized to nitrosomethyl-2-oxopropylamine, the proximate bladder carcinogen.

Administration, Intravesical↗
PubMed1988

The promoting effects of food dyes, erythrosine (Red 3) and rose bengal B (Red 105), on thyroid tumors in partially thyroidectomized N-bis(2-hydroxypropyl)-nitrosamine-treated rats.

The effects of erythrosine (Red 3), rose bengal B (Red 105) and thyroidectomy on the development of thyroid tumor were examined in male Wistar rats treated with N-bis(2-hydroxypropyl)nitrosamine (DHPN). Red 3 and Red 105 were used at 4% in the basal diet and were administered for 19 weeks from week 2 to 20. Thyroidectomy was performed by resection of the left lobe at week 4. Single injection of DHPN was performed intraperitoneally at 280 mg per 100 g body weight at the beginning of the experiment. Red 3 and Red 105 significantly promoted the development of thyroid tumors in thyroidectomized rats given DHPN, but had no significant effect in non-thyroidectomized rats. The incidence of thyroid tumors was 91% in rats with partial thyroidectomy, Red 3 and DHPN, 100% in rats with partial thyroidectomy, Red 105 and DHPN, and 64% in rats with partial thyroidectomy and DHPN. Serum TSH was 5.5 +/- 3.1 ng/ml in rats with partial thyroidectomy, Red 3 and DHPN, 2.1 +/- 2.2 ng/ml in rats with partial thyroidectomy, Red 105 and DHPN, and 1.5 +/- 0.5 ng/ml in rats with partial thyroidectomy and DHPN.

Animals↗
PubMed1988

Strain differences in N-butyl-N-(4-hydroxybutyl)nitrosamine bladder carcinogenesis in rats.

Differences in susceptibility of the urinary bladder epithelium to N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) in various strains were examined. In experiment 1, 5 strains of male rats were given 0.025% BBN in the drinking water for 8 weeks followed by drinking water without BBN for 32 weeks. Analbuminemic rats (NAR) and ACI rats had high incidences of urinary bladder lesions (papillary or nodular hyperplasia, papilloma and carcinoma), F344 and Wistar rats had low incidences, and Sprague-Dawley (SD) rats showed an intermediate incidence. Carcinoma area was largest in NAR rats followed in decreasing order by SD, ACI and F344 rats. The extent of tumor invasion was higher in NAR and ACI rats than in SD rats. In experiment 2, the 5 strains of male rats were administered 0.025% BBN in the drinking water. Some rats from each group were killed after each of weeks 4 and 8. The urinary bladder of ACI and NAR rats given BBN had the most marked lesions observed by scanning electron microscopy, with less marked changes in SD rats. F344 and Wistar rats showed the weakest response. Cytochrome P-450 content of the liver in ACI rats treated with BBN for 4 weeks was significantly higher than those of controls. Cytochrome P-450 and cytochrome b5 contents of the control and BBN-treated rats were significantly higher in ACI and SD rats than in Wistar, F344 or NAR rats. These results indicate that there are strain differences in the urinary bladder response to BBN.

Animals↗
PubMed1988

Effects of phenobarbital and carbazole on carcinogenesis of the lung, thyroid, kidney, and bladder of rats pretreated with N-bis(2-hydroxypropyl)nitrosamine.

Studies were made on potential modifying effects of phenobarbital (PB) and carbazole on tumor development induced by N-bis(2-hydroxypropyl)nitrosamine (DHPN), a wide-spectrum carcinogen in rats. Effects on the lung, thyroid, kidney, bladder and liver were investigated. Male F344 rats were given 0.2% DHPN in their drinking water for 1 week and then 0.05% PB or 0.6% carbazole in their diet for 50 weeks. Control animals were treated with either DHPN or PB or carbazole only. Neither PB nor carbazole affected the incidence or histology of lung tumors. However, PB promoted the development of thyroid tumors and preneoplastic lesions of the liver, while carbazole promoted the induction of renal pelvic tumors.

Adenoma↗
PubMed1990

Inhibitory effects of antioxidants on N-bis(2-hydroxypropyl)nitrosamine-induced lung carcinogenesis in rats.

Potential second-stage modifying effects of 8 antioxidants on lung tumorigenesis initiated by N-bis(2-hydroxypropyl)nitrosamine (DHPN) were examined in male F344 rats. After an initial 2-week treatment with DHPN (0.1% in drinking water), rats were administered one of the antioxidants supplemented in the diet for 30 weeks. Although the incidences of lung adenomas were not affected, those of carcinomas were lowered by 2% butylated hydroxyanisole (BHA, 2 rats/20 rats), 1% butylated hydroxytoluene (BHT, 1/20), 0.8% ethoxyquin (EQ, 3/20) and 1% a-tocopherol (a-TP, 2/20) treatments as compared to the control level (9/20), while 5% sodium L-ascorbate (SA), 0.8% catechol (CC), 0.8% resorcinol (RN), and 0.8% hydroquinone (HQ) did not exert any significant effect on incidence. Quantitative analysis of adenomas and carcinomas (numbers and areas of lesions per unit area of lung section) revealed obvious inhibitory effects of SA, CC, and RN as well as BHA, BHT, EQ, and a-TP. Among the antioxidants, BHT exerted the strongest inhibitory activity. In contrast, DHPN-induced thyroid tumorigenesis was significantly enhanced by BHT (14/20) and EQ (20/20) treatments (control = 5/20). Thus the antioxidants showed opposite effects on lung and thyroid carcinogenesis in the rat.

Adenoma↗
PubMed2000

Lack of modification by environmental estrogenic compounds of thyroid carcinogenesis in ovariectomized rats pretreated with N-bis(2-hydroxypropyl)nitrosamine (DHPN).

The effects of environmental estrogenic compounds, soy isoflavone mixture (SI), genistein (GEN), and nonylphenol (NP), and the possible goitrogen 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX), on thyroid carcinogenesis were investigated in ovariectomized (OVX) female rats. Five-week-old OVX F344 rats were given a single subcutaneous injection of N-bis(2-hydroxypropyl)nitrosamine (DHPN; 2400 mg / kg, body weight) or vehicle alone. Starting 1 week later, GEN (250 or 25 ppm in diet), SI (400 ppm in diet), NP (250 or 25 ppm in diet), MX (30 ppm, in drinking water), sulfadimethoxine (SDM), a known thyroid tumor-promoter (1000 ppm in drinking water), or beta-estradiol 3-benzoate (EB), a synthetic estrogen (0.5 mg in cholesterol pellet, s.c.) were administered for 12 weeks. SDM and EB were included as positive controls. At sacrifice the major organs including the thyroid, pituitary, liver, kidney, uterus, vagina, brain and pancreas were collected and histopathological observation was performed. Thyroid weights were significantly increased (P < 0. 001) only in the SDM treatment group and pituitary weights were elevated with SDM (P < 0.05) and EB (P < 0.001). Kidney and uterus weights were also significantly increased (P < 0.05) by EB. Histopathologically, proliferative lesions of the thyroid were only observed in the SDM treatment group and of the pituitary in the SDM or EB treatment groups. Renal tubule lesions, uterine squamous metaplasia, vaginal keratinization and telangiectasia of pancreatic islets were also observed with EB. There were no organ weight changes or histopathological lesions in the major organs, including the thyroid, in the GEN, SI, MX or NP treatment groups. Our results thus indicated a lack of modifying effects on thyroid carcinogenesis in female OVX rats, in agreement with our previous finding in males.

Aminoacridines↗
PubMed2000

Lack of modifying effects of environmental estrogenic compounds on the development of thyroid proliferative lesions in male rats pretreated with N-bis(2-hydroxypropyl)nitrosamine (DHPN).

The modifying effects of various environmental estrogenic compounds on thyroid carcinogenesis were investigated in a rodent two-stage carcinogenesis model. The compounds examined were a soy isoflavone mixture (SI) and genistein (GEN) as phytoestrogens, nonylphenol (NP) as a xenoestrogen, 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX) as a thyroid carcinogen and sulfadimethoxine (SDM) as a known thyroid tumor promoter. Five-week-old male F344 rats were given a single subcutaneous injection of N-bis(2-hydroxypropyl)nitrosamine (DHPN; 2800 mg / kg, body weight) or the vehicle alone. Starting one week thereafter, GEN (250 or 25 ppm in diet), SI (400 ppm in diet), NP (250 or 25 ppm in diet), MX (30 ppm, in drinking water) or SDM (1000 ppm in drinking water) was administered for 12 weeks. Major organs including the thyroid, pituitary, liver, kidney, testis, brain and pancreas were weighed and histopathological observation was performed. Thyroid weights were significantly increased (P < 0.001) only in the SDM treatment groups, especially with DHPN pretreatment. Kidney weights were slightly increased in the NP or MX treatment groups, albeit without statistical significance. Histopathologically, thyroid proliferative lesions were only observed in the SDM alone or DHPN + SDM group with significant focal hyperplasias, adenomas and adenocarcinomas limited to the combined treatment case. There were no organ weight changes or histopathological lesions in the major organs including the thyroid in the GEN, SI, NP, and MX treatment groups regardless of DHPN pretreatment. Our results thus indicate that the weakly estrogenic compounds GEN, SI and NP and the environmental rat thyroid carcinogen MX do not exert any modifying effects on thyroid carcinogenesis in rats under the present experimental conditions.

Animals↗
PubMed2003

Synergistic interaction between excess caffeine and deficient iodine on the promotion of thyroid carcinogenesis in rats pretreated with N-bis(2-hydroxypropyl)nitrosamine.

The combined effects of caffeine (1,3,7-trimethylxanthine) with iodine deficiency (ID) were examined in a rat two-stage thyroid carcinogenesis model using N-bis(2-hydroxypropyl)nitrosamine (DHPN). Male F344 rats were divided into 6 groups each consisting of 10 animals, and received a single s.c. injection of 2800 mg/kg DHPN. From 1 week after the DHPN initiation, the rats were respectively fed a basal diet in which the protein was exchanged for 20% gluten, containing 1500 ppm caffeine + ID, 300 ppm caffeine + ID, 60 ppm caffeine + ID, 1500 ppm caffeine or ID or a basal diet alone for 12 weeks. Relative thyroid weights were significantly (P < 0.05) increased due to the development of proliferative lesions induced by the ID diet as compared to the DHPN-alone group value, which was enhanced by caffeine, albeit without statistical significance. Relative pituitary weights were significantly (P < 0.05) increased with 300 or 1500 ppm caffeine + ID as compared to the DHPN-alone group value. Serum thyroid stimulating hormone (TSH) levels were slightly increased by ID, an effect which was further enhanced by 300 or 1500 ppm caffeine. Serum thyroxine (T(4)) levels were slightly increased by caffeine or ID alone, but decreased by caffeine with ID. Histopathologically, thyroid follicular carcinomas were found only in the 1500 ppm caffeine + ID group, although thyroid follicular adenomas were detected in all the ID-treated groups. The multiplicity of focal thyroid follicular hyperplasias was significantly (P < 0.05) increased by 1500 ppm caffeine. These results indicate that caffeine may synergistically promote thyroid carcinogenesis with ID partially through a pituitary-dependent pathway in rats, implying the possible implication of routine caffeine intake in the promotion of thyroid carcinogenesis.

Adenocarcinoma, Follicular↗
PubMed1993

Oxygen radicals potentiate the genetic toxicity of tobacco-specific nitrosamines.

Tobacco-specific nitrosamines (TSNAs), nitrosonornicotine (NNN) and 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK), are metabolites of nicotine and the major carcinogens in cigarette smoke. To evaluate the effect of oxygen radicals on TSNA-induced genetic damage, MRC-5 fetal human lung cells were exposed to NNN and NNK (5 mM) and DNA single-strand breaks measured. Both NNN and NNK produced a dose-dependent increase in strand breaks up to 10 mM which was cytotoxic. In combination with enzymatically-generated oxygen radicals, strand breakage increased by approximately 50% for both NNN and NNK. Oxygen radical scavengers (superoxide dismutase, catalase, mannitol) significantly reduced the DNA damage caused by both the TSNAs and TSNAs plus oxygen radicals, suggesting that the genotoxicity is radical-mediated. Because both superoxide dismutase and catalase were protective, the hydroxyl radical may be playing an important role in the mediation of the DNA damage observed.

Carcinogens↗
PubMed1996

The identification of 11 beta-hydroxysteroid dehydrogenase as carbonyl reductase of the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone.

The tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NC), which is generated by nitrosation of nicotine, requires enzymatic activation by cytochrome-P450-mediated alpha-carbon hydroxylation to yield particularly powerful carcinogenic alkylating intermediates. Pyridine-N-oxidation and carbonyl reduction are detoxification pathways, the latter by providing the functional hydroxy moiety necessary for glucuronosylation and final excretion of NC. For more than a decade, the enzyme responsible for NC carbonyl reduction has awaited characterization. In the present study, we demonstrate that the NC carbonyl reductase is identical to 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD), the physiological function of which is the oxidoreduction of glucocorticoids. We conclude that the expression of 11 beta-HSD (together with glucuronosyl transferase) may have profound influence on the carcinogenic potency of NC and that many compounds of endogenous and exogenous origin, which are known to be substrates or inhibitors of 11 beta-HSD, may modulate NNK-induced carcinogenicity by competing for the same enzyme. In light of the known species and tissue differences in the expression of 11 beta-HSD isozymes, important aspects of NNK-induced tumorigenesis, such as metabolic activation versus inactivation or organospecificity, can now be re-evaluated.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1982

Histopathological analysis of preneoplastic changes during N-butyl-N-(4-hydroxybutyl)-nitrosamine-induced urinary bladder carcinogenesis in rats.

Sequential microscopic alterations of the urinary bladder epithelium during carcinogenesis were examined in rats after oral administration of 0.01% or 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN). Simple hyperplasia appeared after 4 weeks of BBN administration. This regressed by 12 weeks after BBN discontinuation but reappeared focally in some areas after 20 weeks and persisted to the termination of the experiment. Preneoplastic papillary or nodular hyperplasia appeared earlier and more frequently in rats treated with 0.05% BBN than in those treated with 0.01%, but these lesions regressed gradually during a prolonged observation period after BBN was discontinued. These results suggest that 2 types of papillary or nodular hyperplasias exist, one reversible and the other irreversible. Tumors appeared earlier in rats treated with 0.05% BBN than in those with 0.01% BBN.

Animals↗
PubMed1986

The biochemistry of nitrates, nitrites, nitrosamines and other potential carcinogens in human saliva.

Human whole saliva protects the oral environment in many different ways from invading pathogenic microorganisms. Human saliva is also capable of inactivating mutagenic and carcinogenic agents by various mechanisms. The peroxidation of these agents is likely to be one of the degrading reactions. However, under certain circumstances some potentially carcinogenic compounds, such as N-nitrosamines, may be generated in whole saliva or--even more likely--in the saliva-gastric juice mixture after swallowing. The formation of N-nitroso compounds requires relatively high intake of nitrate e.g. from vegetable juices. Nitrate is partly reduced to nitrite by oral bacterial enzymes. The nitrosation of various secondary amines is favoured by high salivary (or gastric) concentration of thiocyanate and by low pH. The endogenous generation of N-nitroso compounds may be causally related to the development of oral or gastric cancer.

Carcinogens↗
PubMed1994

Effects of nicotine and tobacco-specific nitrosamines on hamster cheek pouch and gastric mucosa.

Fifty-two hamsters were divided into 6 groups and their cheek pouches treated with either 0.01% NNN, 0.01% NNN and 6% nicotine, 0.01% NNK, 0.01% NNK and 6% nicotine, 6% nicotine, or sesame oil. After painting each pouch 3 times per week for 13 months, the animals were killed and specimens from the cheek pouch and forestomach examined. Cheek pouch epithelium showed more frequent histologic changes, including hyperplasia, hyperkeratosis and, in one animal, moderate dysplasia, when nicotine was combined with NNN than after treatment with NNN (or nicotine) alone. There was a higher frequency of hyperplasia with hyperkeratosis in the forestomach when nicotine was combined with NNK than following NNK, or nicotine treatment alone, and squamous cell papillomas were evident in animals treated with both NNK and nicotine. These results suggest that in mucosal tissues nicotine may enhance the effect of weak carcinogens such as the nitrosamines.

Animals↗
PubMed2003

Comparative metabolism of the tobacco-specific nitrosamines 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol by rat cytochrome P450 2A3 and human cytochrome P450 2A13.

The tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and its carbonyl-reduction product, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), are potent lung carcinogens in rats and are presumed human lung carcinogens. NNK and NNAL are bioactivated to DNA-binding intermediates via hydroxylation of the carbon atoms adjacent to the nitroso moiety (i.e., alpha-hydroxylation) by cytochrome p450s (p450s). Therefore, it is important to delineate which p450s are efficient catalysts of this metabolic transformation. In this study, the kinetic parameters for NNK and NNAL metabolism were determined for two extrahepatic p450s that are expressed in the lung: rat p450 2A3 and human p450 2A13. p450s 2A3 and 2A13 exhibited Vmax values for NNK 4-hydroxylation of 10.8 +/- 0.4 and 13.8 +/- 0.8 pmol min-1 pmol P450-1, respectively; the corresponding Km values were 4.6 +/- 0.5 and 3.6 +/- 0.7 microM. The respective Vmax values for p450 2A3- and 2A13-mediated N-methyl hydroxylation of NNK were 8.2 +/- 0.3 and 4.6 +/- 0.2 pmol min-1 pmol p450-1. These data indicate that p450s 2A3 and 2A13 are both efficient catalysts of the metabolic activation of NNK and are, along with mouse p450 2A5, the best catalysts of this reaction currently known. Both enzymes also catalyzed the alpha-hydroxylation and N-oxidation of NNAL, and its oxidation to NNK. In general, Vmax/Km values for NNAL metabolism were 1 to 2 orders of magnitude lower than those for NNK metabolism, and p450 2A3 was a slightly better catalyst of NNAL metabolism than was p450 2A13. Given the exquisite sensitivity of the rat lung to NNK-induced carcinogenesis, the efficient bioactivation of NNK by rat p450 2A3, and the similar catalytic efficiency of p450s 2A3 and 2A13, p450 2A13 may be an important contributor to NNK bioactivation in the human lung.

Animals↗