DNA ethylation in target and non-target organs of hamsters and rats treated with diethylnitrosamine

Becker, Richard A.; Lu, Shih Shin; Brésil, Henriette; Shank, Ronald C.; Montesano, Ruggero

doi:10.1016/0304-3835(85)90168-5

Cited by 8 publications

(3 citation statements)

References 11 publications

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“…NDEA in Hepatocytes Isolated from Ethanol-Pretreated Rats. During the course of a previous series of experiments (13) we had observed that the metabolism of NDMA and NDEA by isolated hepatocytes led to the incorporation of label from the parent nitrosamine into the acid-insoluble fraction of the incubation mixture, in agreement with the reports of others (1,(14)(15)(16)(17)(18)(19)(20). Figure 1 illustrates the concentration-dependent covalent labeling of acid-insoluble hepatic macromolecules by NDMA and NDEA in hepatocytes isolated from the livers of EtOH-pretreated rats.…”

Section: Labeling Of Cellular Macromolecules By [14c]-ndma and [14c]supporting

confidence: 85%

“…The alkylation of cellular macromolecules by metabolites of NDMA has been demonstrated in vivo in the rat (14,16) and in vitro with guinea pig hepatocytes (18) , rat hepatocytes (15), and hepatic microsomes derived from the rat (1). The alkylation of cellular macromolecules by metabolites of NDEA has been demonstrated in vivo in hamsters and rats (17,20,(23)(24)(25) and with hepatic microsomes derived from the rat (19).…”

Section: Discussionmentioning

confidence: 99%

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Labeling of albumin secreted from isolated rat hepatocytes during the metabolism of N-nitrosodimethyl- and N-nitrosodiethylamine

Gorsky¹,

Hollenberg²

1989

Chem. Res. Toxicol.

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The metabolic activation of N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA) to reactive intermediates which covalently bind to cellular proteins was investigated. Isolated hepatocytes were used to determine whether protein alkylation is random in nature or whether it results in the alkylation of specific proteins. Isolated hepatocytes from rats treated with either ethanol (EtOH) or phenobarbital were incubated with the 14C-labeled nitrosamines for 1-3 h, after which the cells were separated from the incubation medium in order to distinguish secreted proteins from intracellular proteins. SDS-PAGE of the proteins in the medium followed by fluorographic analysis of the gels revealed that a heavily labeled protein was secreted into the medium which represents the predominantly labeled protein. Intracellularly, the major portion of the covalently bound label was found in the region of the gel where the cytochromes P-450 migrate. Pretreatment of the hepatocytes with diethyl maleate and buthionine sulfoximine to decrease the intracellular levels of glutathione had no effect on the labeling, indicating that glutathione does not protect cellular proteins from labeling by these carcinogens. Pretreatment of the cells with D-(+)-galactosamine to inhibit UDP-glucuronyltransferases resulted in a significant decrease in protein labeling by NDEA, suggesting that a glucuronide intermediate may be involved in the activation of NDEA to an alkylating species. The heavily labeled protein secreted into the incubation medium was identified as albumin on the basis of its apparent molecular weight of 66K, as determined by SDS-PAGE, and its cross-reactivity with anti-rat albumin IgG.

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Section: Labeling Of Cellular Macromolecules By [14c]-ndma and [14c]supporting

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Labeling of albumin secreted from isolated rat hepatocytes during the metabolism of N-nitrosodimethyl- and N-nitrosodiethylamine

Gorsky¹,

Hollenberg²

1989

Chem. Res. Toxicol.

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“…Out of 40, 24 rats were given protective doses for 14 consecutive days of 200 mg/kg rosemary extract, 1 g/kg green tea extract and 50 mg/kg rosmarinic acid (Alnahdi, 2012;El-Beih et al, 2015;. The induction of toxicity was initiated with a single intraperitoneal injection of diethyl nitrosamine (DEN) at a dose level of 160 mg/kg body weight (Becker et al, 1985). After eighteen days of the initiation step, the animals were given a single intraperitoneal injection of Fe-NTA at a dose level of 5 mg Fe/kg body weight (Okada et al, 2001).…”

Section: Experimental Designmentioning

confidence: 99%

Nephroprotective effect of green tea, rosmarinic acid and rosemary on N-diethylnitrosamine initiated and ferric nitrilotriacetate promoted acute renal toxicity in Wistar rats

El-Desouky

Mahmoud

Riad

et al. 2019

Interdisciplinary Toxicology

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The present study was designed to investigate the chemoprotective effect of green tea extract (GTE), rosmarinic acid (RA) and rosemary extract (RE) against diethylnitrosamine (DEN) initiated and ferric nitrilotriacetate (Fe-NTA) promoted nephrotoxicity in rats. Forty male rats were categorized into five: Group I included healthy rats, group II received DEN+Fe-NTA, group III received 200 mg/kg b.wt. of RE+DEN+Fe-NTA, group IV received 1 g/kg b.wt. of GTE+DEN+Fe-NTA and group V received 50 mg/kg b.wt. of RA+DEN+Fe-NTA. RE, GTE, RA were given orally for 14 days before single intraperitoneal administration of DEN (160 mg/kg) till the end of the experiment. Eighteen days after DEN, a single intraperitoneal dose of Fe-NTA (5 mg Fe/kg) was administrated to rats to promote nephrotoxicity. The biochemical parameters were analyzed in serum at time intervals while the malondialdehyde (MDA) and tumor necrosis factor-alpha (TNF-α) were assessed in both serum and renal tissues. Kidney from each group was histopathologically examined at time intervals. The administration of Fe-NTA after DEN dose to albino rats resulted in acute nephrotoxicity which was characterized by a highly significant elevation of serum urea, creatinine, uric acid (p=0.000), serum and renal MDA and TNF-α (p=0.000) with vacuolation of epithelial lining renal tubules. The administration of RE, GTE and RA prior to DEN+Fe-NTA treatment significantly ameliorated the observed increased levels of the above mentioned parameters. GTE, RA & RE exerted a protective effect against renal toxicity with GTE showing a more pronounced effect on renal function parameters while RA showed the best antioxidant impact.

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Long-term persistence of DNA alkylation in hamster tissues afterN-nitrosobis(2-oxopropyl)amine

Bax

Pour

Nagel

et al. 1990

J Cancer Res Clin Oncol

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The persistence of 7- and O6-alkylation of guanine in DNA of cell nuclei of male Syrian hamster pancreas, liver, kidneys, lungs [target tissues of N-nitrosobis(2-oxopropyl)amine (BOP)] and salivary glands (nontarget tissue) was studied immunocytochemically 6 h, 1, 3, 7, 14, 28, and 56 days after a single s.c. injection of 20 mg BOP/kg. Conventional antisera raised against O6-methylguanine and imidazole-ring-opened 7-methyl-guanine were used. Persistent alkyl-specific staining was observed for up to 7 days (7-alkylguanine) or 56 days (O6-alkylguanine) in inter- and intralobular duct cells and centro-acinar cells of the pancreas, periportal hepatocytes and bile duct cells of the liver, cells of the proximal convoluted tubules of the renal cortex, and bronchiolar Clara and alveolar cells in the lungs. Both adducts disappeared from centrilobular liver cells within 1 day, from pancreatic acinar cells within 3 days, and from ducts and acini of the submandibular salivary glands within 14 days after BOP treatment. A high level of persistent O6-alkylation of guanine was related with a high tumor incidence only in case of the ductal/ductular system of the pancreas, the main target tissue of BOP-induced carcinogenesis. The relatively weak carcinogenicity of BOP in other tissues with long-term persistence of O6-alkylguanine in DNA indicates that the formation and persistence of DNA alkylation are not sufficient to account for the carcinogenic organotropism of BOP. Additional factors, such as cell proliferation, appropriate promoting stimuli and the (onco)genes critically involved, may be as important as the modification of DNA.

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DNA ethylation in target and non-target organs of hamsters and rats treated with diethylnitrosamine

Cited by 8 publications

References 11 publications

Labeling of albumin secreted from isolated rat hepatocytes during the metabolism of N-nitrosodimethyl- and N-nitrosodiethylamine

Labeling of albumin secreted from isolated rat hepatocytes during the metabolism of N-nitrosodimethyl- and N-nitrosodiethylamine

Nephroprotective effect of green tea, rosmarinic acid and rosemary on N-diethylnitrosamine initiated and ferric nitrilotriacetate promoted acute renal toxicity in Wistar rats

Long-term persistence of DNA alkylation in hamster tissues afterN-nitrosobis(2-oxopropyl)amine

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