Effect of inducers of drug-metabolizing enzymes on diethylnitrosamine metabolism and toxicity

Magour, S.; Nievel, John G.

doi:10.1042/bj1230008pb

Cited by 30 publications

(2 citation statements)

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“…This is consistent with the lack of effect of glutathione depletion on DNA methylation by NDMA in the rat in vivo as reported by Tacchi et al (14). However, one must bear in mind that the pathways involved in the overall disposition of NDEA may differ dramatically from that of NDMA as evidenced by the marked differences in selectivity for different isozymes of P-450 previously demonstrated for these two structurally related nitrosamines (13,36,37).…”

Section: Discussionsupporting

confidence: 90%

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: Discussionsupporting

confidence: 90%

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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“…It is unclear why the numbers of basophilic and other type proliferative lesions were fewer in CARKO mice compared to wild-type mice, including the control group and particularly in the PB group (Figure 6). CAR deficiency might affect the susceptibility to DEN initiation, considering a report that showed PB treatment in rats enhances the metabolism of DEN and attenuates its hepatotoxicity (Magour and Nievel 1971).…”

Section: Discussionmentioning

confidence: 99%

Different Pathways of Constitutive Androstane Receptor–mediated Liver Hypertrophy and Hepatocarcinogenesis in Mice Treated with Piperonyl Butoxide or Decabromodiphenyl Ether

et al. 2013

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The constitutive androstane receptor (CAR) is essential for Cyp2b induction, liver hypertrophy, and hepatocarcinogenesis in response to phenobarbital (PB). Liver hypertrophy with Cyp2b induction is a major mode of action of hepatocarcinogenesis in rodents. However, it remains unclear whether CAR is involved in the response to many other nongenotoxic hepatocarcinogens besides PB. In this study, we investigated CAR involvement in liver hypertrophy and hepatocarcinogenesis of Cyp2b-inducing nongenotoxic hepatocarcinogens, piperonyl butoxide (PBO), and decabromodiphenyl ether (DBDE), using wild-type and CAR knockout (CARKO) male mice. PB was used as the positive control. In the wild-type mice, 4-week treatment with PBO, DBDE, or PB induced hepatocellular hypertrophy with increased Cyp2b10 messenger RNA and Cyp2b protein expression. In CARKO mice, only PBO showed liver hypertrophy with Cyp2b10 and Cyp3a11 induction. After 27-week treatment following diethylnitrosamine initiation, PBO and PB generated many eosinophilic altered foci/adenomas in wild-type mice; however, the lesions were far less frequent in CARKO mice. DBDE increased the multiplicity of basophilic altered foci/adenomas in wild-type and CARKO mice. Our findings indicate that murine CAR plays major roles in hepatocarcinogenesis but not in liver hypertrophy of PBO. DBDE may act via CAR-independent pathways during hepatocarcinogenesis.

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The role of nicotinamide and of certain other modifying factors in diethylnitrosamine carcinogenesis.Fusaria mycotoxins and “spontaneous” tumors in animals and man

Schoental¹

1977

Cancer

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Pretreatment of rats with large doses of nicotinamide, which has been shown to increase the incidence of pancreatic islet-cell tumors after streptozotocin and after hekotrine, appears to promote the development of kidney neoplasias in rats given several doses of diethylnitrosamine. Nicotinamide, one of the B vitamins, and a constituent of NAD coenzymes, will prevent the depletion of NAD coenzymes by alkylating agents. It may protect the animal to some extent from the acute effects of hepatocarcinogens but not from the induction of tumors, although it may change the localization of the latter. The possible mechanisms involved in the action of nicotinamide and of certain other modifyixig agents are discussed. Attention is drawn to the possibility that pituitary, mammary and certain other tumors that sometimes occur among the controls, as well as among experimental animals, may be due to the occasional presence in laboratory animal diets of estrogenic and/or toxic secondary metabolite8 of the field fungi, Fusaria. Mycotoxins, such as zearalenone and the trichothecehes, are also likely to Contaminate human foods; this could explain why multiple tumors in man occur mainly in the sex organs and in the digestive tract.

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Effect of inducers of drug-metabolizing enzymes on diethylnitrosamine metabolism and toxicity

Cited by 30 publications

References 1 publication

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

Different Pathways of Constitutive Androstane Receptor–mediated Liver Hypertrophy and Hepatocarcinogenesis in Mice Treated with Piperonyl Butoxide or Decabromodiphenyl Ether

The role of nicotinamide and of certain other modifying factors in diethylnitrosamine carcinogenesis.Fusaria mycotoxins and “spontaneous” tumors in animals and man

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