Haemoglobin values in venous and skin puncture blood.
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Adolescent↗
Biomedical subjects
L M Anderson
Publications and source records attributed to L M Anderson.
Ahr locus phenotype in congenic mice influences hepatic and pulmonary DNA adduct levels of 2-amino-3-methylimidazo[4,5-f]quinoline in the absence of cytochrome P450 induction.
The potent food mutagen/carcinogen 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) undergoes metabolic N-hydroxylation by cytochromes P450, including cytochrome P450 1A2, followed by generation of an unstable ester catalyzed by acetyltransferases; promutagenic DNA adducts result. Genetic polymorphisms in these enzymes have been implicated in human cancer risk related to arylamine exposure. We investigated the effects of Ahr locus and acetylator polymorphisms on 32P-postlabeled IQ/DNA adducts in lungs and livers of female C57BL/6 mice congenic for slow acetylation and/or Ahr-nonresponsiveness; some groups were pretreated with beta-naphthoflavone (beta NF), a cytochrome P450 1A inducer. Total adducts in lung were doubled by beta NF pretreatment in Ahr-responsive mice only and consisted of < or = 30% adduct 2 and < or = 60% adduct 3. In contrast, in Ahr-nonresponsive mice, adducts 2 and 3 were each < or= 7% of the total. Livers of noninduced Ahr-responsive mice formed 6-18-fold more adducts than those of nonresponsive mice. This striking difference was not due to altered levels of cyp1a-2, as indicated by specific enzyme assays and immunoblotting, and was not accompanied by a comparable increase in the ability of liver preparations to activate IQ to a mutagen in the Ames test. Pretreatment of responsive mice with beta NF to induce cyp1a-1 and cyp1a-2 led to a reduction in liver adduct levels. Acetylation phenotype also had a significant effect in Ahr-responsive mice, with 3-fold more adducts in slow than in rapid acetylators. These results indicate that in uninduced mice, the normal Ah receptor facilitates formation of IQ/DNA adducts in liver and alters the profile of adducts in lung, via an unknown mechanism, whereas the Ah receptor-dependent enzyme induction reduces adducts in liver, probably due to increased detoxification, but increases them in lung.
Acetylation↗
DNA damage studies related to the assessment of the role of N-nitroso compounds in human cancer.
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Carcinogens↗
O6-methylguanine DNA adduct formation and modulation by ethanol in placenta and fetal tissues after exposure of pregnant patas monkeys to N-nitrosodimethylamine.
Perinatal nitrosamine exposures may contribute to childhood cancer risk. To test primate fetal susceptibility to formation of cancer initiation-related DNA adducts from nitrosamines, pregnant patas monkeys were given 1.0 or 0.1 mg/kg N-nitrosodimethylamine. Appreciable levels of the promutagenic O6-methylguanine adduct occurred in placental and fetal liver DNA after both doses and were lower but detectable in other fetal tissues after the higher dose. Coadministered ethanol (1.6 g/kg) reduced adducts in placenta and fetal liver by one-half and increased levels in other fetal tissues to the same degree. Thus, primate placenta and fetal tissues have a significant, ethanol-modulated capacity to activate N-nitrosodimethylamine, supporting implication of nitrosamines in human perinatal carcinogenesis and of alcohol as a modulating factor.
Animals↗
Promotion of N-nitrosodiethylamine-initiated hepatocellular tumors and hepatoblastomas by 2,3,7,8-tetrachlorodibenzo-p-dioxin or Aroclor 1254 in C57BL/6, DBA/2, and B6D2F1 mice.
To investigate the hypothesis that tumor promotion by chlorinated aromatic hydrocarbons involves Ah receptor occupation and subsequent induction of cytochromes P-450 1a-1, effects of Aroclor 1254 or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) were examined in N-nitrosodiethylamine-initiated mice with different Ah receptor phenotype. Levels of cytochromes P-450 1a and 2b were measured by enzyme assay and Western immunoblots. Males of the C57BL/6, DBA/2, or (C57BL/6 x DBA/2)F1 (hereafter referred to as "B6D2F1") strain were initiated with a single i.p. dose of N-nitrosodiethylamine (90 mg/kg body weight), followed by either multiple doses of TCDD (0.05 micrograms/kg) weekly or Aroclor 1254 chronically in the diet (100 ppm) for 20 weeks, and then no treatment for 24 weeks. Lung tumor incidence or multiplicity was not altered by either of the promoters. Liver tumor incidence was similar among the three strains after N-nitrosodiethylamine alone (14, 21, and 21%, respectively). In DBA/2 mice, TCDD neither induced Cyp 1a nor promoted liver tumors. Aroclor caused an 8-fold induction of hepatic Cyp 2b, which was its maximum at the 12-week time point but did not promote tumors. Inductions of hepatic Cyp 1a by TCDD and 1a and 2b by Aroclor were similar in C57BL/6 and B6D2F1 mice, but tumor promotion responses were quite different. Dietary Aroclor significantly promoted liver tumors in C57BL/6 mice (59 versus 14%) but not in B6D2F1 mice (24 versus 21%). Repeated TCDD promoted only in B6D2F1 mice (52 versus 21%) and not in C57BL/6 mice (19 versus 14%). Thus, whereas these data confirm that a functional Ah receptor is required for liver tumor promotion, the degree of activation as measured by induction of Cyp 1a is not directly related to the degree of tumor-promoting capability. Other genetic factors must play a role in mediating the final tumor outcome.
Animals↗
DNA adducts of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) in colon, bladder, and kidney of congenic mice differing in Ah responsiveness and N-acetyltransferase genotype.
Heterocyclic amines, suspected as cancer initiators, require metabolic activation to exert genotoxicity. The food carcinogen 2-amino-3-methyl-imidazo[4,5-f]quinoline (IQ) undergoes activation via N-hydroxylation by cytochrome P450 1A2, followed by O-esterification by N-acetyltransferase. We examined the effects of the Ah locus and acetylator polymorphisms (implicated in human colon and bladder cancer risk) on levels of 32P-postlabeled IQ-DNA adducts in C57BL/6 mice congenic for slow acetylation and/or Ah nonresponsiveness. Some were pretreated with beta-naphthoflavone (beta NF), an inducer of cytochromes P450 1A. Guanine adducts were detected in all organs, the predominant one corresponding to N2-(deoxyguanosine-8-yl)-IQ. In the kidney, beta NF pretreatment reduced total adducts by 50% in Ah-responsive animals (P = 0.021); the Ah or acetylator phenotype did not otherwise affect total adducts. In the colon of Ah-nonresponsive animals, rapid acetylators had 3-fold more adducts than slow acetylators (P = 0.0001, vehicle-pretreated; P = 0.0031, beta NF-pretreated). In Ah-responsive mice of either acetylator phenotype, beta NF pretreatment reduced total adducts in the colon by 70% (P = 0.0003). A significant interaction of phenotypes occurred in the bladder; beta NF-pretreatment caused a 2.5-fold increase in adducts but only in the Ah-responsive, rapid acetylator mice. In sum, these polymorphisms influenced the level of IQ-DNA adducts in the kidney, urinary bladder, and colon in complex ways.
Acetylation↗
Transplacental carcinogenesis by cisplatin in F344/NCr rats: promotion of kidney tumors by postnatal administration of sodium barbital.
Transplacental carcinogenic effects of cis-dichlorodiammineplatinum (cis-DDP) in F344 rats were investigated. Pregnant F344 rats were given a single i.p. administration of either cis-DDP (5 mg/kg body wt; group 1) or saline only (group 2) on Day 18 of gestation. Offspring of groups 1 and 2 were randomly and equally divided into two subgroups: 1a, 1b and 2a, 2b, respectively. Beginning at 4 weeks of age, offspring in groups 1b and 2b received 500 ppm of sodium barbital (NaBB) in diet, while those in groups 1a and 2a received normal diet. The experiment was terminated at 79 weeks of age. A low incidence (2/19; 10.5%) of male offspring exposed to transplacental cis-DDP (group 1a) developed renal cell adenomas. Postnatal administration of NaBB significantly enhanced this incidence (10/22; p < 0.01) in cis-DDP-initiated offspring. Also, multiple kidney tumors were more common in group 1b than any other group and three animals in this group developed frank renal cell carcinomas. cis-DDP, administered transplacentally, was a complete carcinogen for rat liver as the incidence of hepatocellular adenomas was significantly higher in offspring exposed transplacentally to cis-DDP than in those exposed to saline (20/82 vs 3/75; p < 0.05). NaBB, a known promoter of hepatocellular carcinogenesis in adult rats initiated with N-nitrosodiethylamine, failed to promote liver carcinogenesis initiated by transplacental cis-DDP. Tumors of the central nervous system (3/82; gliomas) and peripheral nervous system (2/82; schwannomas) were found only in offspring exposed transplacentally to cis-DDP. Thus, cis-DDP, administered transplacentally, was a strong initiator of renal cell tumors and a complete carcinogen for multiple organs in rat offspring.
Animals↗
Dosimetry of O6-methylguanine in rat DNA after low-dose, chronic exposure to N-nitrosodimethylamine (NDMA). Implications for the mechanism of NDMA hepatocarcinogenesis.
Groups of female Wistar Furth/NCr rats, aged 6 weeks or 7 months at the start of the experiment, were administered drinking water containing N-nitrosodimethylamine (NDMA) for up to 28 days at concentrations in the range 0.2-2.64 p.p.m., resulting in daily intakes in the range 28-372 micrograms/kg/day at age 10 weeks. The levels of the premutagenic DNA adduct O6-methylguanine (O6-meG) in liver and blood leukocyte DNA were measured at different times during this exposure as well as on the days immediately following cessation of exposure. The adduct was found to accumulate rapidly in both tissues, reaching within 2-7 days steady states in the range 0.08-0.45 mumol/molG, similar in young and adult animals. Accumulation of O6-meG in blood leukocytes was approximately 30% lower than in the liver. Following cessation of NDMA treatment, adducts were lost rapidly from the DNA of both tissues, with an apparent t1/2 of approximately 19-23 h for the liver and 30-35 h for blood leukocytes. No change in liver O6-alkylguanine-DNA alkyltransferase (AGT) took place throughout this treatment. The steady-state adduct levels were approximately linearly related to NDMA dose-rate, except that a clear break (corresponding to a 2.6-fold lower slope) was observed at dose rates > 0.4 p.p.m. (approximately 56 micrograms/kg/day). This dose-response relationship is in contrast to the sharp increase in the liver tumour induction in rats chronically treated with similar concentrations of NDMA reported by Peto et al. (Cancer Res., 51, 6415-6451) and suggests that accumulation of O6-meG cannot by itself account for the hepatocarcinogenic efficacy of NDMA in the rat. Following i.g. administration of single doses of NDMA in a range approximately corresponding to the daily intake during the above mentioned chronic exposure study (25, 50 or 100 micrograms/kg), repair of O6-meG followed sharply biphasic kinetics in both liver and blood leukocytes. In the liver, an initial rapid phase (t1/2 approximately 1.5-1.7 h) was followed by much slower repair (t1/2 approximately 20.7-24.9 h) despite the absence of any change in AGT. Extrapolation of the two segments of the repair kinetics plots back to 0 time suggests that approximately 52-61% of the adducts originally formed in the liver and 33-35% of those formed in blood leukocytes belonged to the rapidly repaired category.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
Promotion of N-nitrosodimethylamine-initiated mouse lung tumors following single or multiple low dose exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin.
The environmental contaminant, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), is highly toxic to several rodent species and may have adverse health effects in exposed human populations. Further, TCDD has been shown to be a potent liver tumor promoter in the rat after repeated administration. These studies were conducted to determine the tumor promoting capability of TCDD in the Swiss mouse following single or multiple exposures. Following tumor initiation with N-nitrosodimethylamine (NDMA; 25 mg/kg), animals were given either a single dose (1.6, 16 or 48 micrograms/kg) or repeated injections (0.05 microgram/kg/week for 20 weeks) of TCDD and sacrificed at 52 weeks of age. Neither NDMA nor TCDD caused an increase in incidence of liver tumors. NDMA induced lung tumors in 100% of animals, with 12 +/- 0.1 tumors/mouse. The multiplicity of lung tumors was significantly increased by low dose TCDD treatment, with 20 +/- 2.6 tumors/mouse following a single 1.6 micrograms/kg dose (P = 0.016) and 18 +/- 1.7 (P = 0.031) following repeated 0.05 microgram/kg doses (x 20). Higher doses of TCDD did not increase multiplicity of lung tumors and, in fact, may have been toxic to the lungs of NDMA-treated mice, as evidenced by the infiltration of pigmented macrophages. These data demonstrate the potent tumor promoting capability of TCDD in mouse lung.
Animals↗
Fetal mouse susceptibility to transplacental carcinogenesis: differential influence of Ah receptor phenotype on effects of 3-methylcholanthrene, 12-dimethylbenz[a]anthracene, and benzo[a]pyrene.
Genetic backcrosses of C57BL/6 and DBA/2 mice were used to examine the influence of maternal and fetal polymorphisms at the Ahr locus on susceptibility to transplacental carcinogenesis by 3-methylcholanthrene, 7,12-dimethylbenz[a]anthracene, and benzo[a]pyrene. (C57BL/6 x DBA/2) F1 mothers were backcrossed to DBA/2 males, and DBA/2 females to F1 males to produce both Ahr-responsive (Ah+) and nonresponsive (Ah-) fetuses carried by mothers that were themselves either Ah+ or Ah-. 3-Methylcholanthrene was given intragastrically on gestation days 13-18 and 7,12-dimethylbenz[a]anthracene or benzo[a]pyrene on day 17 as a single intraperitoneal dose. Ahr phenotype was determined by the zoxazolamine sleeping time test after beta-naphthoflavone pretreatment at 6 weeks of age. The offspring were examined for tumours at 1 year. Both 3-methylcholanthrene and 7,12-dimethylbenz[a]anthracene treatments resulted in a two- to five-fold greater incidence and multiplicity of lung and liver tumours in the Ah+ offspring compared with that in Ah- littermates. By contrast, there was no difference between Ah+ and Ah- offspring with regard to numbers of tumours caused by benzo[a]pyrene. Maternal Ahr phenotype appeared to play a role also, in that the offspring of the Ahr-responsive F1 mothers developed fewer tumours per unit dose than those of the nonresponsive DBA/2 mothers. The effect of maternal phenotype on risk was three- to five-fold. Fetal and maternal phenotype combined yielded a 10- to 20-fold risk differential for transplacental carcinogenesis by the methylated compounds, with greatest risk experienced by responsive fetuses in nonresponsive mothers, and least by nonresponsive progeny of responsive mothers.
9,10-Dimethyl-1,2-benzanthracene↗
Has the use of cervical, breast, and colorectal cancer screening increased in the United States?
This report describes trends in reported breast, cervical, and colorectal cancer screening within the US population from 1987 to 1992. Data from the 1987 and 1992 Cancer Control Supplements of the National Health Interview Survey were analyzed to determine use of Pap smears by women aged 18+; of mammography and clinical breast examination by women aged 50+; and of proctoscopy, digital rectal examination, and fecal occult blood testing among men and women aged 50+. Use of mammography doubled between 1987 and 1992 while Pap smear use changed very little. Use of the three colorectal cancer screening modalities increased but levels remained low. Usage trends were also assessed in relation to several sociodemographic factors. Disparities in screening reported in 1987 according to income and education persisted in 1992.
Aged↗
Suppression of pulmonary P4502b and induction of hepatic, intestinal and kidney P4501a-1 and 1a-2 in the Ah-responsive and non-responsive mouse by Aroclor 1254.
1. Investigations in our laboratory have demonstrated a rapid suppression of the P4502b isoform in mouse lung, concomitant with significant induction of this enzyme in liver from these same animals. The current study was designed to determine whether the suppression by polychlorinated biphenyls of pulmonary P4502b required the presence of a functional Ah receptor, and additionally to delineate the time course of the induction responses to Aroclor 1254 in the liver, kidney, and intestine of the AH-responsive and non-responsive mouse. 2. P450s were quantified by specific enzyme assay and immunoblot in liver (1a-1, 1a-2, 2b), lung (1a-1, 1a-2), kidney (1a-1, 1a-2, 2b) and small intestine (1a-1, 2b) of C57 and DBA animals at varying times (48 h-12 weeks) following a single intraperitoneal dose of Aroclor 1254 (250 mg/kg). 3. The suppression of constitutive P4502b in the lung by Aroclor was observed in both strains, but was more prominent over a longer time course in the non-responsive animals. P4502b enzyme activity was increased in the liver and intestine of both strains of mouse; however, there was a significantly greater response to Aroclor in the C57 animals. These data indicate that the AH receptor does not participate in the suppression of pulmonary P4502b, and suggests that the regulation of inducible P4502b in liver and intestine is quantitatively different between these two strains of mouse. 4. P4501a was predictably induced in all tissues examined from the C57 animal, but was largely unaffected by PCBs in the DBA strain. P4501a-2, which is also regulated by the Ah receptor, was highly induced in the liver of the responsive strain, and also increased approximately two-fold in the liver of the non-responsive animals. Kidney P4501a-2 was also modestly increased by Aroclor, only in the responsive mouse.
Animals↗
Promotion by polychlorinated biphenyls of lung and liver tumors in mice.
Polychlorinated biphenyls (PCB), which are tumor promoters, have been found in human tissues for decades. Their contribution to cancer risk may only now start to appear, due to long human cancer latency and the nature of tumor promotion. Epidemiological associations have been seen between PCB exposure or tissue content and cancer at several sites. In rodents, tumor promotion by PCBs has been little studied in tissues other than liver. Previously, in an experiment modeling infant carcinogen exposure following PCBs received in milk, lung and liver tumors, initiated neonatally in mice by the environmental nitrosamine N-nitrosodimethylamine (NDMA), were promoted by later treatment with Aroclor 1254. The present study was undertaken to confirm and characterize the effects of Aroclor 1254 on tumor number, latency, size and malignancy. Male Swiss mice were given NDMA on postnatal day 4 and Aroclor 1254 (250 mg/kg) on day 8, and killed at intervals. Eight PCB congeners were quantified in the carcasses. Incidences of mice with NDMA-initiated lung tumors at 28 weeks of age were increased 2.5-fold by PCBs. Multiplicities of lung tumors were enhanced four-fold by PCBs at 28 and 52 weeks. By 72 weeks tumor numbers were similar in the NDMA-only and NDMA-PCB groups. Liver tumors first occurred in significant numbers at 52 weeks and only in mice receiving both NDMA and PCBs. As for the lung, at 72 weeks the incidence was high in both the NDMA-only and NDMA-PCB groups. Sizes of tumors and liver carcinoma incidence were not altered by PCB treatment. Carcass analysis revealed a significant positive association between lung tumor numbers at 28 weeks and relative percentage of 2,2',4,4',5-pentachlorobiphenyl, with no other correlations. The results confirm that PCBs promote lung as well as liver tumors, by triggering the early appearance of latent initiated tumors otherwise presenting in old age.
Animals↗
Periodic acid Schiff reaction in childhood lymphoblastic leukaemia. The Medical Research Council Working Party on Childhood Leukaemia.
AIMS: To assess the prevalence and degree of periodic acid Schiff (PAS) positivity in blast cells from children with lymphoblastic leukaemia (ALL); its association with other disease characteristics; and its clinical importance in predicting the outcome of treatment. METHODS: Marrow slides from entrants to a large United Kingdom multicentre ALL trial (UKALL X) were batch processed and assessed blind for PAS positivity by one morphologist. Patients were classified into groups A, B, and C, corresponding to less than 1% PAS positive cells, 1-10%, and over 10%, respectively. Their PAS pattern was then compared with other clinical and pathological features of ALL and with treatment outcome. RESULTS: Slides from 921 children were examined of which 371 (40%) were categorised as group A, 324 (35%) as group B, and 226 (25%) as group C. There was a clear association between the presence of blast cell vacuoles on Romanowsky staining and PAS positivity. Group A (PAS negative) patients included a disproportionate excess of those with L2 morphology, those under 2 or over 6 years of age, those with an initial white cell count over 50 x 10(9)/l, those with a T or null cell immunophenotype, and those with chromosomal abnormalities other than "high hyperdiploidy". Four years from diagnosis, group C patients had an 8% disease free survival advantage over those in group A (2p = 0.01). This was irrespective of initial white cell count, but not of immunophenotype or the presence of vacuoles. CONCLUSIONS: Strong PAS positivity is a feature of "common" ALL and is particularly associated with blast cell vacuoles. It does occasionally occur in other disease subtypes with or without vacuoles. It predicts a better response to current treatment, but not independently of other cell characteristics.
Adolescent↗
Transplacental carcinogenicity of cisplatin: initiation of skin tumors and induction of other preneoplastic and neoplastic lesions in SENCAR mice.
cis-Dichlorodiammineplatinum (cis-DDP), an anticancer agent sometimes used in pregnant women for the treatment of malignant ovarian and uterine tumors, was tested for transplacental carcinogenic and/or tumor-initiating effects in SENCAR mice. Pregnant mice were given a single i.p. injection of either cis-DDP (7.5 mg/kg body weight) in 2.5% NaCl or the same weight-adjusted volume of NaCl (5 ml/kg body weight) on day 17 of gestation. Offspring were delivered and raised by their natural mothers until weaning at 3 weeks of age. Starting at week 4, offspring in experimental groups received topical applications of 2 micrograms 12-O-tetradecanoylphorbol-13-acetate (TPA) in acetone twice a week for 20 weeks while those in control groups received only acetone (0.2 ml/application) for the same duration. The experiment was terminated at 25 weeks of age. A high incidence (18 of 37; 48.7%) of papillomas was observed in offspring exposed transplacentally to cis-DDP and postnatally to TPA, while only 10% (4 of 40) of offspring exposed to TPA alone developed such tumors (P < 0.0002). Although no skin tumors were observed without TPA promotion, transplacental administration of cis-DDP resulted in development of thymic lymphomas, lung tumors, and proliferative kidney lesions in offspring. These results provide the first evidence that cis-DDP can initiate and/or induce preneoplastic and neoplastic lesions in multiple tissues transplacentally.
Animals↗
Enhancement of tumorigenesis by N-nitrosodiethylamine, N-nitrosopyrrolidine and N6-(methylnitroso)-adenosine by ethanol.
Inclusion of 10% ethanol with 6.8 ppm N-nitrosodiethylamine in the drinking water of strain A male mice resulted in a 4-fold enhancement of multiplicity of lung tumors and a 16-fold increase in incidence of fore-stomach tumors, compared with carcinogen alone. Given with 40 ppm N-nitrosopyrrolidine, ethanol caused a 5.5-fold increase in lung tumor multiplicity. The inclusion of 15% ethanol with N6-(methylnitroso)adenosine, given orally to Swiss female mice, led to reduced body weights and shortened survival time related to hemangiosarcoma occurrence or increased incidence of thymic lymphoma, depending on dose of carcinogen. The data provide additional support for the proposal that co-administered ethanol increases the tumorigenicity of nitrosamines by blocking hepatic first-pass clearance.
Animals↗
Specific induction of hepatic cytochrome P4501a-2 in C57BL/6 and DBA/2 mice treated with 2-amino-3-methylimidazo[4,5-f]quinoline (IQ).
The food mutagen/carcinogen 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) is activated by cytochrome p4501a-2 via N-hydroxylation; various P450s may contribute to detoxification via ring hydroxylation. Alterations in P450 levels by IQ treatment might therefore influence its toxicity. To examine the role of Ah locus genotype on the biochemical effects of IQ, C57BL/6 (AhbAhb; p450Ia-1/2 inducible) and DBA/2 (AhdAhd, noninducible) mice of both sexes were given IQ at varying doses, with different vehicles and routes of administration. Livers taken after 24 hours were assessed for total cytochrome p450 and activities of ethoxyresorufin-O-deethylase (EROD, a p4501a-1 activity, inducible in Ahb mice), methoxyresorufin-O-demethylase (MROD, a p4501a-2 activity), and benzyloxyresorufin-O-dealkylase (BzROD, an activity of p4502b). There was little effect on total cytochrome p450, but all three enzyme activities were often induced, a maximum of 2.5-fold, in both sexes and in DBA/2 as well as C57BL/6 mice. However, Western immunoblot analysis with monoclonal antibodies demonstrated an increase only in p4501a-2 protein. p4501a-1 remained undetectable. A monoclonal antibody to p4502-b recognized one protein band in liver microsomes from males and two bands in female mice of both strains. Amounts of these proteins were not altered by IQ treatment. Thus, IQ specifically, if moderately, induces its activating enzyme, p4501a-2, in a process that was not clearly related to Ah responsiveness.
Animals↗
Metabolism of the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in the patas monkey: pharmacokinetics and characterization of glucuronide metabolites.
The metabolism of the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) was examined in the patas monkey, in order to provide further information about NNK metabolic pathways in primates. Female patas monkeys were given i.v. injections of [5-3H]NNK, and metabolites in serum and urine were analyzed by HPLC. Metabolism by alpha-hydroxylation of NNK was rapid and extensive, and the products of this pathway, 4-hydroxy-4-(3-pyridyl)butyric acid and 4-oxo-4-(3-pyridyl) butyric acid, accounted for a relatively large proportion of serum and urinary metabolites at all time points. This is significant because the formation of these products is associated with modification of DNA by NNK. The other major metabolic pathway was carbonyl reduction to 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), which detected both unconjugated and diastereomeric O-glucuronides. One of these glucuronides had been previously identified in rat urine, but the other diastereomer, which was the more prevalent of the two in serum and urine, had not been observed in studies of NNK metabolism in rodents. It was characterized by its spectral properties, by enzymatic hydrolysis to NNAL, and by derivatization of the released NNAL enantiomer with (R)-(+)-alpha-methylbenzylisocyanate. The two NNAL glucuronides accounted for 15-20% of the urinary metabolites in monkeys given 0.1 micrograms/kg NNK, which is similar to a smoker's dose, suggesting their use as dosimeters of NNK exposure in humans. Pharmacokinetic parameters were consistent with those observed in previous studies of nitrosamines, and varied predictably with body weight of five species. The results of this study have provided new insights relevant to assessing human metabolism of NNK.
Animals↗