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K Randerath

Publications and source records attributed to K Randerath.

At least 73 records · Page 4Linked to original sources
PubMed1992

Sex-specific modulation of hepatic covalent DNA modifications (I-compounds) by the cytochrome P450 inducer, pregnenolone-16 alpha-carbonitrile.

I-compounds are recently discovered, age-dependent covalent DNA modifications, which are detectable by 32P-postlabeling assay for DNA adducts. The effects of the catatoxic antiglucocorticoid, pregnenolone-16 alpha-carbonitrile (PCN), on hepatic and renal I-compound levels have been studied in male and female Sprague-Dawley rats together with the levels of microsomal cytochrome P450 and rates of ethylmorphine N-demethylation. PCN (50 mg/kg ip) was dissolved in corn oil and administered to rats once daily for 4 days, and animals were killed at 1 day or 8 days after the last treatment. Hepatic and renal I-compounds were analyzed by 32P-postlabeling in control and PCN-treated animals at both time points. Microsomal cytochrome P450 and ethylmorphine N-demethylase activities were also determined. Total levels of liver nonpolar and polar I-compounds were reduced in female rats by 37 and 51%, respectively, compared to controls, at 1 day. Ten out of sixteen individual I-compounds were also markedly reduced in female rat liver DNA as a result of PCN administration. In contrast to females, total levels of liver I-compounds were not significantly altered in males by PCN at 1 day; however, two individual I-compounds were lowered. I-compound levels recovered 8 days after termination of PCN treatment in both males and females. Total levels of renal I-compounds were not affected by PCN treatment in either males or females. [3H]Methylthymidine incorporation studies showed an increase in mean DNA synthesis rate at 1 day in liver of both males and females, but this was significant in males only. Marked induction of hepatic microsomal cytochrome P450 (2.2-fold) and ethylmorphine N-demethylase (4.0-fold) activity was observed in female rats treated with PCN at 1 day as compared to controls. The extent of induction of these enzymes was much higher in females than males. At 8 days the levels of cytochrome P450 and ethylmorphine N-demethylase activity had returned to uninduced values. The results are consistent with a pivotal role for PCN-inducible cytochrome P450 in the metabolism of I-compounds.

Animals↗
PubMed1992

Modulation of DNA modification (I-compound) levels in rat liver and kidney by dietary carbohydrate, protein, fat, vitamin, and mineral content.

I-compounds are DNA modifications detected by 32P-postlabeling that increase with age in rodents without known carcinogen exposure. Diet type (natural ingredient versus purified) greatly influences patterns and levels of I-compounds. To test the hypothesis that I-compound formation is affected, also, by dietary macro- and micronutrients, effects of carbohydrate, protein, fat, vitamin, and mineral content on rat liver and kidney I-compounds were determined. Female Sprague-Dawley rats were fed basic or modified AIN-76A purified diets for 3-6 months. High protein (HP) diet (50%, w/w) increased I-compound levels in liver but not kidney. High carbohydrate (HC) diet (78%) produced a significant increase in the polar as well as total I-compound levels in both tissues. High fat diets (20%) elicited significantly lower levels of liver I-compounds than HC, HP, and basic diets. There were few significant differences between high polyunsaturated (safflower oil) and saturated fat (lard) diet groups. No qualitative differences in I-compound profiles were observed in either tissue. In rats fed basic diet supplemented with vitamins and/or minerals, increased vitamin content reduced the levels of polar I-compounds in liver. No extra diet-induced adducts were observed; all effects were of a quantitative nature. These data provide direct evidence that nutrients significantly influence I-compound levels and support the hypothesis that normal metabolism of nutrients leads to the production of small amounts of DNA-reactive electrophiles. These observations suggest a novel mechanism where nutrient composition of the diet may play a role in development of neoplasia and other adverse health effects.

Aging↗
PubMed1992

Formation of ribonucleotides in DNA modified by oxidative damage in vitro and in vivo. Characterization by 32P-postlabeling.

Oxygen free radicals generated by the interaction of Fe2+ and H2O2 (Fenton reaction) are capable of reacting with DNA bases, which may induce premutagenic and precarcinogenic lesions. Products formed in DNA by such reactions have been characterized as hydroxylated derivatives of cytosine, thymine, adenine, and guanine and imidazole ring-opened derivatives of adenine and guanine. As shown here by 32P-postlabeling, incubation of DNA under Fenton reaction conditions gave rise to additional oxidation products in DNA that were characterized as putative ribonucleosides by enzymatic hydrolysis of the oxidized DNA, 32P-postlabeling, and co-chromatography in multiple systems with authentic markers. Formation of these products in DNA was enhanced by the presence of L-ascorbic acid in the reaction mixtures and their total amounts were similar to those of the major DNA oxidation product, 8-hydroxy-2'-deoxyguanosine. The ribonucleoside guanosine was also formed in kidney DNA of male rats treated with ferric nitrilotriacetate, a renal carcinogen. It is postulated that ribonucleotides alter conformation and function of DNA and thus their presence in DNA may lead to adverse health effects.

Adenosine Triphosphate↗
PubMed1992

Natural dietary ingredients (oats and alfalfa) induce covalent DNA modifications (I-compounds) in rat liver and kidney.

Mammalian tissue DNA has recently been found, via 32P postlabeling, to contain complex profiles of age-dependent bulky carcinogen adductlike covalent modifications, which have been termed I-compounds, referring to their apparent indigenous origin without exposure to exogenous carcinogens. I-compound patterns are highly species, sex, tissue, and diet specific. As shown here, the presence of certain plant ingredients in diet, i.e., ground oats and alfalfa meal, significantly contributed to the formation of these DNA derivatives. Six groups of weanling female Sprague-Dawley rats were fed one of the following diets for three months: a natural ingredient diet containing neither oats nor alfalfa (Wayne MRH 22/5 Rodent Blox), Wayne diet supplemented with oats or alfalfa or both, a purified semisynthetic diet (AIN-76A), and AIN diet supplemented with oats. The natural ingredient diet produced more complex patterns and higher levels of I-compounds than purified diet in both liver and kidney DNA. Supplementation of either diet with oats elicited the formation of four additional oats-specific I-compounds in liver DNA. Oats and alfalfa, individually and in combination, tended to significantly raise nonpolar and diminish polar I-compound levels. To determine whether the oats-related extra spots were derived from mycotoxin contamination, two groups of rats were fed either Wayne diet or Wayne diet containing zearalenone (0.05 mg/kg) for three weeks. Zearalenone significantly increased the uterine weight but did not induce any DNA adduct formation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Effects of phenobarbital on I-compounds in liver DNA as a function of age in male rats fed two different diets.

The age-dependent effects of diet and of phenobarbital (PB), a known promoter of hepatocarcinogenesis, on indigenous DNA adducts (I-compounds) were studied by the 32P-post-labeling technique. Late-gestation female Sprague-Dawley rats were fed either AIN-76A semisynthetic or Teklad cereal-based diet. At 21 days after birth, the male pups were weaned and continued on the diets, with half of each dietary group receiving 0.05% PB mixed into the diet for 2, 4 and 8 months. Age-dependent increases in I-compound levels were observed. In addition, both the levels of individual I-compounds and the overall number of I-compounds were greater in rats fed the Teklad cereal-based diet than in those fed the AIN-76A diet. Independent of the parent diet, PB administration reduced the levels of the majority of I-compounds in a time-dependent manner. This effect of PB was detected earlier in the Teklad-fed than in the AIN-76A-fed group. In contrast to the I-compounds, a second group of spots, termed reverse I-compounds, declined between 2 and 4 months and, especially in AIN-76A-fed animals, tended to increase when PB was administered. It is hypothesized that alterations of DNA modification patterns may play a role in diet-modified hepatocarcinogenesis promoted by PB.

Age Factors↗
PubMed1992

Effects of cytochrome P450 inducers on I-compounds in rat liver and kidney DNA.

I-compounds are covalent DNA modifications presumably derived from endogenous electrophiles. To investigate the possible role of cytochrome P450 in I-compound metabolism, groups of female Sprague-Dawley rats (225-250 g) were treated i.p. with vehicle or cytochrome P450 inducers, i.e. 80 mg/kg phenobarbital (PB), 20 mg/kg 3-methylcholanthrene (MC) or 50 mg/kg pregnenolone-16 alpha-carbonitrile (PCN), once daily for 4 days. DNA synthesis rate was measured via [3H]methylthymidine incorporation. DNA adducts and I-compounds in liver and kidney were analyzed 1 and 8 days after the last treatment. Total liver and kidney microsomal cytochrome P450 content and activities of representative drug-metabolizing enzymes for PB, MC and PCN, i.e. benzphetamine N-demethylase, ethoxycoumarin O-deethylase (ECD) and erythromycin N-demethylase, were also determined in all groups. PCN caused significant depletion of total non-polar I-compounds at 1 day, compared to controls. Levels of several individual I-spots in liver were differentially reduced by each of the three inducers at 1 day. Most I-spots were restored to control levels at 8 days. Kidney I-compounds were not affected by PB or PCN, but MC reduced the level of one non-polar individual I-compound at 1 day. Except for the expected DNA adduct formation from MC, there were no qualitative changes in profiles of postlabeled modified nucleotides. Total cytochrome P450 content in liver microsomes and activities of individual P450 enzymes were significantly increased by treatment with each of the inducers at 1 day. This was, however, not the case at 8 days in PB- and PCN-treated livers. MC-treated rats, on the other hand, displayed elevated levels of liver cytochrome P450 and ECD at 8 days. In kidney, PB and PCN did not elicit induction of P450 and individual enzymes, but MC increased total P450 content and ECD activity at 1 day, and ECD activity alone at 8 days. These results suggest a major role for cytochrome P450 enzymes in the metabolism of I-compounds.

7-Alkoxycoumarin O-Dealkylase↗
PubMed1991

Induction of rat liver DNA alterations by chronic administration of peroxisome proliferators as detected by 32P-postlabeling.

The mechanisms of the hepatocarcinogenicity of non-mutagenic peroxisome proliferators, i.e. compounds used as hypolipidemic drugs and industrial plasticizers, are not sufficiently understood. To gain more information on the mechanism of their action, the chronic effects of two structurally diverse peroxisome proliferators on rat-liver DNA were investigated by the 32P-postlabeling assay. Male F-344 rats (1.5 month old) were fed ciprofibrate (0.025%) in the diet for 2, 5, 8, and 16 months or Wy-14643 (0.1%) for 18 months. Liver DNA from individual treated animals (3-4 per group) and age-matched controls was analyzed by the nuclease P1/bisphosphate version of the 32P-postlabeling assay. Three distinct types of exposure-related DNA alterations were observed: (i) A significant reduction of the age-dependent accumulation of I-compounds (putative indigenous DNA modifications) (type 1), (ii) adduct-like DNA derivatives induced by the treatments (type 2), and (iii) as yet structurally uncharacterized radiolabeled material occupying substantial areas of DNA adduct maps and accumulating in an exposure time-dependent manner (type 3). DNA from liver tumors generated by these agents displayed only traces of I-compounds, lacked all but one adduct-like derivatives, and had no type 3 alterations. Thus, in contrast to the non-mutagenicity of peroxisome proliferators in short-term assays, chronic administration of these compounds led to DNA alterations that were detectable by 32P-postlabeling assay.

Affinity Labels↗
PubMed1991

Effects of aging and caloric restriction on I-compounds in liver, kidney and white blood cell DNA of male Brown-Norway rats.

Rodent tissues display species-, strain-, sex- and tissue-specific adduct-like DNA modifications termed I-compounds, which increase with age, are modulated by diet and are presumably derived from indigenous metabolic intermediates. We have explored whether I-compounds are affected by caloric restriction, which is known to extend life span and retard age-related degenerative and neoplastic diseases. Male Brown-Norway rats were fed NIH-31 diet ad libitum (AL). Calorically restricted (CR) rats received 60% of AL consumption, starting at 3.5 months. DNA was analyzed by 32P-postlabeling at 1, 4, 8, 12, 16 and 24 months of age in liver, kidney and white blood cells. I-compounds in AL liver and kidney exhibited complex tissue specific profiles; I-compound levels increased with age, plateaued between 8 and 18 months depending on tissue and diet and were 8.7 (liver) and 27.4 (kidney) modifications in 10(8) nucleotides at 24 months, thereby exceeding the corresponding 1-month values by 3.7- and 16.6-fold. CR resulted in similar profiles but did not diminish age-related increases, rather I-compound levels in CR liver and kidney were increased by about 70% and 30% versus age-matched AL rats. White blood cells exhibited few I-compounds and at low levels; age-related increases were small overall but more pronounced in CR rats. Higher I-compound levels in CR animals, which were presumably a consequence of metabolic effects elicited by CR, thus correlated with extended life span and, therefore, may be beneficial, in agreement with previous findings showing an association between reduced I-compound levels and hepatocarcinogenesis as well as organ susceptibility to diseases.

Aging↗
PubMed1991

Short-term effects of the tumor promoting polychlorinated biphenyl mixture, Aroclor 1254, on I-compounds in liver, kidney and lung DNA of male Sprague-Dawley rats.

The effects of a tumor promoting polychlorinated biphenyl mixture, Aroclor 1254, on I-compounds (tissue, species and sex dependent DNA modifications that increase with age in untreated rodents) were studied by 32P-postlabeling in male Sprague-Dawley rat liver, kidney, and lung DNA. Aroclor 1254 was dissolved in corn oil and intraperitoneally (i.p.) injected (2 x 500 mg/kg, 2 weeks apart) into 3-month-old rats. Control rats were given corn oil. Groups of 3 animals were sacrificed at 2 and 6 weeks after the second injection of corn oil or Aroclor 1254. At both time points Aroclor 1254-treated rats had significantly lower body weights and higher liver weights while kidney and lung weights were unaffected. Thymidine incorporation into liver and lung DNA was significantly increased at both time points, while kidney DNA showed a small decrease at 2 weeks. Treatment resulted in significant reductions (ranging from 29 to 100%) of each of nine liver I-spots at 2 and 6 weeks. In treated rats there was no decrease in kidney I-spots at 2 weeks, while the levels of only two out of ten kidney spots were reduced by 42-91% at 6 weeks. At 2 weeks three out of seven and at 6 weeks four out of seven lung I-spots were lowered by 51-100% in the Aroclor 1254-treated rats. Thus the effects decreased in the order liver greater than lung greater than kidney. Since Aroclor 1254 has been reported to be a tumor promoter in liver and lung but not kidney, these results suggest a correlation between organ specific promotion of carcinogenesis by Aroclor 1254 and the reduction of DNA I-compounds.

Animals↗
PubMed1991

Postlabeling analysis of polycyclic aromatic hydrocarbon-DNA adducts in white blood cells of foundry workers.

Blood samples were obtained from 61 volunteers working in a Finnish iron foundry who were exposed to carcinogenic polycyclic aromatic hydrocarbons and from 19 control subjects not known to be exposed to these chemicals. Foundry workers were categorized into high, medium, or low exposure groups, based on their exposure levels to airborne benzo[a]pyrene (BaP) (high greater than 0.2, medium 0.05-0.2, low less than 0.05 micrograms BaP/m3 air). Aromatic adducts were determined in white blood cell DNA from exposed and unexposed subjects using 32P-postlabeling. There was a highly significant correlation between the estimated exposure and adduct levels as determined by analysis of variance. The levels of adducts found in the high and medium group samples ranged from 5 to over 20 adducts in 10(8) DNA nucleotides. No effects due to age, sex, or the smoking habits of the subjects were observed. Within each group, the SEM appeared rather small. This study demonstrates the utility of the 32P-postlabeling assay to assess human exposure to known and unknown environmental aromatic genotoxicants.

Adult↗
PubMed1991

Specific reduction of I-compound levels in DNA from spontaneous hepatomas of 22-24 month old male C3H mice.

As previously shown by 32P-postlabeling, I-compound levels are reduced in target tissue DNA of animals exposed to one of several non-genotoxic hepatocarcinogens, e.g. 2,3,7,8-tetrachlorodibenzo-p-dioxin, carbon tetrachloride, peroxisome proliferators and choline-devoid diet. I-compound levels are further reduced, sometimes to undetectable levels, in chemically induced, transplantable rat (Morris) hepatomas and hepatocellular carcinomas induced by peroxisome proliferators or choline-devoid diet. The current study investigated I-compounds in spontaneous hepatic adenomas of genetically susceptible male C3H mice. DNA samples from individual tumors, background livers (non-tumor bearing lobe from tumor bearing mouse) and non-tumor bearing normal livers taken from 22-24 month old animals were analyzed by 32P-postlabeling. I-compound profiles were qualitatively comparable among the three types of tissues. However, levels of most I-compounds were 2.6-5.0 times lower in tumors than in background liver and non-tumor bearing normal liver. There were virtually no differences between background liver and normal liver. Taken together with the previously reported I-compound deficiency in carcinogen-induced hepatomas, the present observations on genetically initiated neoplasms suggest that this phenomenon may play a role in hepatocarcinogenesis and maintenance of neoplasia.

Aging↗
PubMed1991

DNA adduct formation in liver and kidney of male Syrian hamsters treated with estrogen and/or alpha-naphthoflavone.

Chronic administration of estrogens to male Syrian hamsters induces kidney tumors. Co-administration of estrogen plus alpha-naphthoflavone (ANF) suppresses this kidney carcinogenesis but induces liver tumors instead. In an attempt to elucidate the mechanism of the switch from estrogen-induced kidney to liver carcinogenesis in response to ANF treatment, patterns of kidney and liver DNA adducts were investigated by 32P-postlabeling analysis and compared to controls. Chronic treatment of hamsters with ANF alone or in combination with estradiol resulted in a flavone-specific DNA adduct pattern in livers of these animals. These spots, adducts 1 and 2, on 32P-postlabeling maps were taken as evidence of covalent ANF-DNA modifications. The kidney-specific estrogen-induced indirect DNA adducts, observed previously in hamsters treated chronically with estrogen, occurred in renal but not hepatic DNA of animals treated with estradiol alone or in combination with ANF. Pretreatment of hamsters with ANF for 3 days decreased by 75-80% the hepatic and renal diethylstilbestrol (DES)-DNA adducts, which are formed after injection of a single large dose of DES. It is concluded from these changes in DNA adduct patterns and levels that estrogen quinone-DNA adduction may play an etiological role in estrogen-induced kidney cancer. The prevention of estrogen-induced kidney tumors by ANF co-treatment may be a consequence of the decrease in renal concentrations of these adducts in response to ANF. Hepatic concentrations of estrogen quinone-DNA adducts also decrease, but ANF-DNA adducts, observed only in liver, may assume an etiological role in the induction of hepatomas.

Animals↗
PubMed1991

Modulation by dietary vitamin E of I-compounds (putative indigenous DNA modifications) in rat liver and kidney.

I(indigenous)-compounds are age-related, carcinogen adduct-like, putative indigenous DNA modifications detectable by 32P-postlabeling assay in untreated animals. To investigate the origins of these DNA derivatives, we examined the effects of dietary vitamin E, a natural antioxidant, on I-compounds of rat liver and kidney DNA. Weanling female Sprague-Dawley rats were fed Draper's diets containing 0, 100, 1000, or 10,000 mg/kg alpha-tocopheryl acetate for 6 mo. The DNA from four individual rats of each group was analyzed by a nuclease P1-enhanced version of the 32P-postlabeling assay for DNA adducts. The amount of vitamin E in the liver was measured by high performance liquid chromatography. Rats fed vitamin E-deficient diet (0 mg/kg) showed identical profiles and similar levels of I-compounds as those fed the 100 mg/kg diet. Most I-spots were significantly intensified and one tissue-specific extra spot was found in both liver and kidney DNA of rats fed the 1000 or 10,000 mg/kg vitamin E diet. However, one of the five major I-spots detected in the kidney was weaker in the 1000 and 10,000 mg/kg groups than in the 0 and 100 mg/kg groups. These results show that formation of most I-compounds was not affected by vitamin E-deficient diet, and that long-term feeding of diet containing high levels of vitamin E may cause metabolic alterations leading to an increased formation of DNA-reactive (potentially mutagenic or carcinogenic) electrophiles.

Animals↗
PubMed1991

Sexual dimorphism of the chromatographic profiles of I-compounds (endogenous deoxyribonucleic acid modifications) in rat liver.

DNA of all tissues studied thus far in untreated mammals contains as yet structurally unidentified, covalent modifications termed I (indigenous)-compounds, which are detectable by the 32P postlabeling assay for DNA adducts and increase with age. The purpose of this study was to determine the effects of sex, gonadectomy, and androgen administration on I-compound profiles and levels in order to gain insight into the factors involved in the biosynthesis of these DNA modifications. Liver DNA from various groups of 6-month-old Sprague-Dawley rats (untreated or gonadectomized males and females; animals with or without gonadectomy treated with testosterone propionate) was analyzed by a nuclease P1-enhanced version of the 32P postlabeling assay. Hepatic I-compound profiles of untreated animals exhibited pronounced sexual dimorphism. In addition to a number of I-compounds that differed quantitatively between sexes, 7 female-specific and 1 male-specific I-compounds were observed. In female rats, the total level amounted to 112 I-compounds in 10(9) DNA nucleotides and exceeded the level in males by 3-fold. Castration feminized and ovariectomy masculinized I-compound profiles and levels. Neonatal testosterone propionate failed to restore the male pattern of I-compounds lost by neonatal castration, so that an androgen-imprinting mechanism did not appear to be involved in the maintenance of the male I-compound phenotype and the suppression of the female pattern. Testosterone propionate administered to intact female animals lowered total I-compound levels significantly. The results indicate that estrogens play a dominant role in regulating sex-dependent formation of I-compounds in rat liver. The dependence of I-compound formation on both age and sex hormones suggests that the levels of these DNA modifications are developmentally controlled.

Animals↗
PubMed1990

Persistent reduction of indigenous DNA modification (I-compound) levels in liver DNA from male Fischer rats fed choline-devoid diet and in DNA of resulting neoplasms.

Reduced levels of putative indigenous DNA modifications (I-compounds) in liver DNA of male Fischer 344 rats fed a hepatocarcinogenic choline-devoid (CD) diet for up to 7 mo have been previously reported. To investigate the persistence of this effect and possible relationships between I-compounds and hepatocarcinogenesis, liver DNA modifications of tumor-free male rats fed a CD diet for 3, 6, 9, or 12 mo, followed by a choline-supplemented (CS) diet to 16 mo, were compared with those in rats fed exclusively the CD or CS diet for 16 mo by a 32P-postlabeling assay. In addition, DNA from nontumorous and tumorous tissues of rats fed the CD diet similarly for 12 or 16 mo was analyzed. It was found that total I-compound levels in male rats consecutively fed CD and CS diets for various lengths of time were similar to those in rats fed the CD diet only and significantly lower than those in rats fed the CS diet only. I-compound levels of nontumorous regions from tumor-bearing livers were 73% of those in tumor-free livers from the same treatment group. I-compound levels were further reduced, some to undetectable levels, in tumor tissues and exhibited an inverse relationship with tumor incidence. The patterns and levels of I-compounds in liver DNA of CD diet-fed female rats, which were not susceptible to CD diet-induced hepatocarcinogenesis, on the other hand, were not significantly different from those of controls. Thus, reduction of I-compound levels by feeding a CD diet lasted for many months after changing from the CD to the CS diet. Whether this persistent DNA alteration contributes to carcinogenesis remains to be determined.

Animals↗
PubMed1990

Association between diet and age-related DNA modifications (I-compounds) in rat liver and kidney.

Mammalian tissue DNA has recently been found, by 32P-postlabeling, to contain complex profiles of age-dependent and tissue-specific bulky carcinogen adduct-like modifications, which have been termed I-compounds since they appeared to arise indigenously, in the absence of exposure to exogenous carcinogens. I-compounds are presumably formed by reaction of metabolically produced, as yet unidentified, electrophiles with DNA. In order to shed light on the origin of I-compounds, we have examined whether diet affects the levels and profiles of I-compounds. Weanling female Sprague-Dawley rats were provided with either one of three natural ingredient diets (rodent chows) or a purified diet (AIN-76A) for up to 6 months. Liver and kidney DNAs were analyzed after 0, 3, and 6 months of feeding, by a nuclease P1-enhanced 32P-postlabeling assay. Rats fed natural ingredient diets showed a greater complexity and 2.5-6.4-fold higher levels of I-compounds in the DNA of both tissues than rats fed purified diet. In addition, less marked qualitative and quantitative differences were noted among rats fed different chow diets. Three classes of I-compounds were identified: class A, I-spots common to both kinds of diet; class B, chow-specific spots; and class C, AIN-76A-specific spots. Liver and kidney shared some I-compounds, mostly belonging to class A, but there were also tissue-specific spots. These observations indicate a novel intimate link between diet and DNA modifications and are consistent with the hypothesis that the formation of I-compounds proceeds via normal metabolism of nutrients and other natural dietary components, leading to the production of small amounts of DNA-reactive electrophiles. Because of their DNA adduct-like character, I-compounds may play a critical role at the interface between nutrition and cancer.

Aging↗
PubMed1990

32P-assay of DNA adducts in white blood cells and placentas of pregnant women: lack of residential wood combustion-related adducts but presence of tissue-specific endogenous adducts.

Residential wood combustion (RWC), which has been increasingly used as a heating source, is of health concern because emissions from RWC contain carcinogenic polycyclic aromatic hydrocarbons (PAH). To assess health risk, the possible formation of PAH-DNA adducts in white blood cells (WBC) and placentas of nonsmoking women exposed to RWC smoke during pregnancy was measured by a nuclease P1-enhanced 32P-postlabeling assay having a sensitivity limit of one lesion per 10(9-10) DNA nucleotides. DNA samples isolated from 12 exposed specimens (8 WBC, 4 placentas) and 13 unexposed control specimens (8 WBC, 5 placentas) were hydrolyzed to mononucleotides, which were then 32P-labeled and separated by high-resolution thin-layer chromatography. Comparison of autoradiograms of exposed DNA samples with those of controls failed to show exposure-related adducts. All placental DNA maps exhibited one major (47 +/- 10%) and 12 minor extra spots, however, that were not seen on WBC-DNA maps. These derivatives corresponded to an average of 12 (+/- 6) modifications in 10(9) nucleotides. Similarly, WBC DNA showed four spots that were absent in placental DNA and were not quantified because of their low levels. Neither placental nor WBC DNA adducts coincided chromatographically with the product formed by the reaction of benzo(a)pyrene diol epoxide I with N2 of guanine in DNA. Although these results suggest that RWC smoke does not elicit detectable levels of aromatic DNA adducts in humans, lack of evaluation of RWC exposure levels leaves some uncertainty in this conclusion. The results, however, clearly show that placental and WBC DNA contain covalent modifications that are unrelated to RWC exposure. These DNA derivatives may be caused by ingestion and/or inhalation of, or skin contact with, low levels of environmental genotoxicants or may arise from endogenous electrophiles of as yet unknown origin.

Benzo(a)pyrene↗