Aryl Sulfotransferase IV Deficiency in Rat Liver Carcinogenesis Initiated with Diethylnitrosamine and Promoted withN-2-Fluorenylacetamide or Its C-9-Oxidized Metabolites

Malejka-Giganti, Danuta; Ringer, David P.; Vijayaraghavan, Palaniswamy; Kiehlbauch, Charles C.; Kong, Jin

doi:10.1006/exmp.1997.2211

Cited by 7 publications

(3 citation statements)

References 28 publications

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“…The sulfotransferase enzymes are soluble enzymes found in many tissues including liver, kidney, gut and platelets and catalyze the sulfation of drugs such as paracetamol, isoprenaline and salicylamide and many steroids. It appears that the sulphotransferase exist in multiple enzyme forms with the steroid sulfating enzymes being distinct from the sulfotransferases responsible for drug conjugation reaction [354][355][356]. It should be emphasized that sulfate conjugation reactions are not as widespread or as of quantitative importance as glucuronide conjugation reactions, due in part to the limited bioavailability of inorganic sulfate and hence PAPS.…”

Section: Sulfate Conjugationmentioning

confidence: 99%

Drug-Metabolizing Enzymes Mechanisms and Functions

Sheweita

2000

CDM

213

128

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Drug-metabolizing enzymes are called mixed-function oxidase or monooxygenase and containing many enzymes including cytochrome P450, cytochrome b5, and NADPH-cytochrome P450 reductase and other components. The hepatic cytochrome P450s (Cyp) are a multigene family of enzymes that play a critical role in the metabolism of many drugs and xenobiotics with each cytochrome isozyme responding differently to exogenous chemicals in terms of its induction and inhibition. For example, Cyp 1A1 is particularly active towards polycyclic aromatic hydrocarbons (PAHs), activating them into reactive intermediates those covalently bind to DNA, a key event in the initiation of carcinogenesis. Likewise, Cyp 1A2 activates a variety of bladder carcinogens, such as aromatic amines and amides. Also, some forms of cytochrome P450 isozymes such as Cyp 3A and 2E1 activate the naturally occurring carcinogens (e.g. aflatoxin B1) and N-nitrosamines respectively into highly mutagenic and carcinogenic agents. The carcinogenic potency of PAHs, and other carcinogens and the extent of binding of their ultimate metabolites to DNA and proteins are correlated with the induction of cytochrome P450 isozymes. Phase II drug-metabolizing enzymes such as glutathione S-transferase, aryl sulfatase and UDP-glucuronyl transferase inactivate chemical carcinogens into less toxic or inactive metabolites. Many drugs change the rate of activation or detoxification of carcinogens by changing the activities of phases I and II drug-metabolizing enzymes. The balance of detoxification and activation reactions depends on the chemical structure of the agents, and is subjected to many variables that are a function of this structure, or genetic background, sex, endocrine status, age, diet, and the presence of other chemicals. It is important to realize that the enzymes involved in carcinogen metabolism are also involved in the metabolism of a variety of substrates, and thus the introduction of specific xenobiotics may change the operating level and the existence of other chemicals. The mechanisms of modification of drug-metabolizing enzyme activities and their role in the activation and detoxification of xenobiotics and carcinogens have been discussed in the text.

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Section: Sulfate Conjugationmentioning

confidence: 99%

Drug-Metabolizing Enzymes Mechanisms and Functions

Sheweita

2000

CDM

213

128

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“…2-Acetylamino-9-‰uorenone (AAF＝O): AAF＝O was synthesized by acetylation of 2-amino-9-‰uorenone (Sigma-Aldrich, St. Louis, MO, USA) by acetylation with acetic anhydride and pyridine. TLC on silica gel was developed with 5z methanol-dichloromethane; mp 231.0-232.09 C (233-2369 C) (5). To prevent oxidation of N-hydroxylamine, all procedures were performed in a nitrogen atmosphere.…”

Section: Methodsmentioning

confidence: 99%

Activation Mechanism of 2-Acetylamino-9-fluorenone as a Mutagen in Salmonella typhimurium

Inami

Mochizuki

2008

Genes and Environment

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2-Acetylamino‰uorene (AAF) is a procarcinogen and its activation mechanisms have been investigated in detail. AAF was metabolized to 2-acetylamino-9-‰uorenone (AAF ＝O) and 2-acetylamino-9-‰uorenol by S9 mix. The mutagenicity of AAF＝O in the presence of S9 mix was equal in potency to that of AAF in Salmonella typhimurium TA1538, but the activation mechanism of AAF＝O was poorly reported. In this study, we investigated possible ultimate species derived from AAF＝O; N-hydroxy-2-acetylamino-9-‰uorenone (N-OH-AAF＝O), N-acetoxy-2-acetylamino-9-‰uorenone (N-OAc-AAF＝O), N-hydroxy-2-amino-9-‰uorenone (N-OH-AF＝O), and N-acetoxy-2-tri‰uoroacetylamino-9-‰uorenone (N-OAc-TFAAF＝O), a model compound for N-acetoxy-2-amino-9-‰uorenone (N-OAc-AF＝O), were synthesized and their mutagenicity was examined in S. typhimurium TA1538. The activation mechanism in S. typhimurium TA1538 was also investigated. The compounds in order of decreasing mutagenicity are N-OAc-TFAAF＝OÀN-OH-AF＝OÀN-OAc-AAF＝OÀ N-OH-AAF＝O. AAF＝O is at least partially responsible for the mutagenicity of AAF, since a small amount of AAF is oxidized to AAF＝O in the presence of S9 mix. Furthermore we suggest that an ultimate active species of AAF＝ O in S. typhimurium is N-OAc-AF＝O, with the same activation manner as AAF.

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“…In the study of hepatocarcinogenesis in animal models, efforts to overcome this problem have been made by protocols that use surgical interventions, such as partial hepatectomy [8,9], and toxic agents, such as acetylaminofluorene [9,10], to shorten the premalignant phase. Major drawbacks include the level of invasiveness, the large numbers of controls required and the complexities of the protocols that interfere with the interpretation of the experimental results.…”

Section: Introductionmentioning

confidence: 99%

Administration of Diethylnitrosamine in the Immediate Postnatal Period Coupled with Exposure to a Choline Deficient Diet Accelerates Hepatocarcinogenesis in the Rat

Hemmings

Strickland²

2002

Cell Physiol Biochem

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The objectives of this study were to determine if the combination of: i. neonatal administration of diethylnitrosamine and ii. subsequent feeding of a choline deficient diet could accelerate hepatic premalignancy in the rat. The presence and size of premalignant nodules and the activity of the liver cancer enzyme marker g-glutamyltranspeptidase (gGT) were used as indicators of hepatic premalignancy. Three day old Fisher 344 rats were administered sc, saline or diethylnitrosamine (DENA): 100 mg/Kg. These were divided into choline sufficient (CS) and choline deficient (CD) groups with diets introduced to dams. On postnatal day 21 rats were weaned onto CS or CD diets. Rats in choline sufficient saline-injected (CS), choline sufficient DENA-injected (CS+DENA), choline deficient saline-injected (CD) and choline deficient DENA-injected (CD+DENA) groups were assessed on day 86. Livers of CS and CS+DENA rats were normal in appearance. Livers of CD rats were paler; those of CD+DENA rats contained visible, large, tan liver nodules. Identical results were observed in both sexes. Liver gGT activity was low and comparable in rats of CS and CS+DENA groups. Relative to liver homogenate gGT activity in the CS group, liver homogenate gGT was increased in the CD group: 14.5 fold in males and 18 fold in females; and further increased in the CD+DENA group: 78 fold in males and 54 fold in females. Plasma g-glutamyltranspeptidase exhibited the same trends as liver. The CD+DENA group demonstrated the largest increase in activity: 158 fold in males; 199 fold in females over that in the CS group. Male and female rats belonging to CS and CS+DENA groups were euthyroid; those in CD and CD+DENA groups were hypothyroid. Compared to hormone levels in the CS group, in the CD group, decreases in T3 were: 27% in males and 13% in females; decreases in T4 were: 29% in males and 5.6% in females. Compared to hormone levels in the CS groups, in the CD+DENA groups, decreases in T3 were: 25% in males and 18% in males; decreases in T4 were: 31% in males and 25% in females. Plasma glucose levels were comparable in rats of CS and CS+DENA groups. Relative to these levels, plasma glucose levels in rats of CD and CD+DENA groups were decreased 30% in males and females. Plasma transaminase levels were low and comparable in all groups. The protocol developed accelerated hepatocarcinogenesis in the Fischer 344 rat. In CD+DENA male and female rats, it produced, in 86 days, visible, large hyperplastic lesions displaying high levels of gGT and high levels of plasma gGT that are consistent with being at a well developed advanced premalignant stage of hepatocarcinogenesis without any sign of toxicity.

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Aryl Sulfotransferase IV Deficiency in Rat Liver Carcinogenesis Initiated with Diethylnitrosamine and Promoted withN-2-Fluorenylacetamide or Its C-9-Oxidized Metabolites

Cited by 7 publications

References 28 publications

Drug-Metabolizing Enzymes Mechanisms and Functions

Drug-Metabolizing Enzymes Mechanisms and Functions

Activation Mechanism of 2-Acetylamino-9-fluorenone as a Mutagen in Salmonella typhimurium

Administration of Diethylnitrosamine in the Immediate Postnatal Period Coupled with Exposure to a Choline Deficient Diet Accelerates Hepatocarcinogenesis in the Rat

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