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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Aldehydes are highly reactive molecules that may have a variety of effects on biological systems. They can be generated from a virtually limitless number of endogenous and exogenous sources. Although some aldehyde-mediated effects such as vision are beneficial, many effects are deleterious, including cytotoxicity, mutagenicity, and carcinogenicity. A variety of enzymes have evolved to metabolize aldehydes to less reactive forms. Among the most effective pathways for aldehyde metabolism is their oxidation to carboxylic acids by aldehyde dehydrogenases (ALDHs). ALDHs are a family of NADP-dependent enzymes with common structural and functional features that catalyze the oxidation of a broad spectrum of aliphatic and aromatic aldehydes. Based on primary sequence analysis, three major classes of mammalian ALDHs--1, 2, and 3--have been identified. Classes 1 and 3 contain both constitutively expressed and inducible cytosolic forms. Class 2 consists of constitutive mitochondrial enzymes. Each class appears to oxidize a variety of substrates that may be derived either from endogenous sources such as amino acid, biogenic amine, or lipid metabolism or from exogenous sources, including aldehydes derived from xenobiotic metabolism. Changes in ALDH activity have been observed during experimental liver and urinary bladder carcinogenesis and in a number of human tumors, including some liver, colon, and mammary cancers. Changes in ALDH define at least one population of preneoplastic cells having a high probability of progressing to overt neoplasms. The most common change is the appearance of class 3 ALDH dehydrogenase activity in tumors arising in tissues that normally do not express this form. The changes in enzyme activity occur early in tumorigenesis and are the result of permanent changes in ALDH gene expression. This review discusses several aspects of ALDH expression during carcinogenesis. A brief introduction examines the variety of sources of aldehydes. This is followed by a discussion of the mammalian ALDHs. Because the ALDHs are a relatively understudied family of enzymes, this section presents what is currently known about the general structural and functional properties of the enzymes and the interrelationships of the various forms. The remainder of the review discusses various aspects of the ALDHs in relation to tumorigenesis. The expression of ALDH during experimental carcinogenesis and what is known about the molecular mechanisms underlying those changes are discussed. This is followed by an extended discussion of the potential roles for ALDH in tumorigenesis. The role of ALDH in the metabolism of cyclophosphamidelike chemotherapeutic agents is described. This work suggests that modulation of ALDH activity may an important determinant of the effectiveness of certain chemotherapeutic agents.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Aldehyde dehydrogenases and their role in carcinogenesis. 152 60

Dichloroacetic acid (DCA) has recently been shown to increase significantly the incidence of hepatic adenomas (HAs) and hepatocarcinomas (HCs) in male B6C3F1 mice. Although little is known about the mechanism of DCA carcinogenesis, chronic ingestion of the compound in drinking water induces primarily hyperplastic nodules (HNs) prior to the appearance of HAs and HCs. Given the putative preneoplastic potential of the HNs, we undertook this study to determine the role of the HNs in the progression of DCA-induced hepatocarcinogenesis. This role was assessed by detecting the expression of five different tumor markers: p21 ras, p39 c-jun, phosphotyrosine, tumor-associated aldehyde dehydrogenase and alpha-fetoprotein, all known from previous studies to be expressed more often in neoplastic liver lesions than in normal liver. Tumor marker expression was detected by immunohistochemical methods using formalin-fixed, paraffin-embedded sections of normal B6C3F1 mouse liver, and DCA-induced HNs, HAs and HCs. The results demonstrated that, except for the c-jun marker, HNs expressed the markers significantly less often than either HAs or HCs. Equal expression of c-jun occurred in any of the three lesion types. Although these results could be used to argue that no relationship existed between HNs and later-appearing HAs and HCs, those HNs that were marker positive contained small nests of marker-positive hepatocytes among a field of normally appearing unstained hepatocytes. No similar nests of marker-positive cells were detected in any area of normal liver outside the HNs. Also very few altered hepatic foci (AF) were detected with these markers or with hematoxylin and eosin, or with histochemical stains for ATPase or glucose-6-phosphatase deficiencies. These results suggested that these nests within some HNs were areas of transformed, or neoplastic hepatocytes. Phenotypic heterogeneity analysis, in which the number of tumor markers co-expressed by any given lesion was examined, confirmed a significantly greater percentage of HAs and HCs expressing multiple markers than HNs. Those HNs that expressed multiple markers, however, expressed at the same frequency as HAs and HCs and the expression was confined to the same nests of cells. Taken together, these data suggest that these nests of marker-positive cells within the HNs were neoplastic and could develop into later-appearing HAs and/or HCs. The absence of marker expression in normal liver and limited expression in the few AF indicates that the HNs may be the only significant preneoplastic lesion in DCA-induced hepatocarcinogenesis.
Carcinogenesis 1991 Aug
PMID:The role of hyperplastic nodules in dichloroacetic acid-induced hepatocarcinogenesis in B6C3F1 male mice. 186 Jan 58

The rate of formation and the persistence of an exocyclic guanine adduct formed in DNA of rodents treated with various doses of N-nitrosopyrrolidine (NPYR) have been determined. NPYR is hepatocarcinogenic to the rat and forms a covalent adduct in liver DNA; this adduct was recently identified as 2-amino-6,7,8,9-tetrahydro-9-hydroxypyrido[2, 1-f]purine-4[3H]-one. Dose-dependent amounts of adduct formed in liver, kidney and lung DNA of rats, hamsters and mice given oral doses (56-900 mg/kg body wt) of NPYR. The persistence of the adduct in DNA after administration of low doses of NPYR to rats was greatest in the target organ, i.e. the liver; at high doses of NPYR, adduct levels in DNA changed little over a period of at least 72 h. In the hamster, in which NPYR is carcinogenic to the lung but apparently not the liver, the adduct level in liver DNA was an order of magnitude greater than in lung or kidney DNA for a dose of NPYR of 225 or 900 mg/kg body wt; persistence of the adduct in lung DNA was only slightly longer than in liver DNA. The formation and persistence of the 7,8-pyridoguanine adduct in the rat appeared to be consistent with the organotropy of this carcinogen, but this was not true for the hamster, a species that seems to be more resistant to induction of liver and kidney cancer by this carcinogen. Imidazole, an inhibitor of microsomal amine oxidase, and disulfiram, an inhibitor of aldehyde dehydrogenase, decreased metabolic activation of NPYR to an alkylating intermediate; inducers and inhibitors of cytochrome P450 monooxygenases had little effect on the metabolic activation of NPYR to an alkylating agent.
Carcinogenesis 1991 Apr
PMID:Formation and persistence of a DNA adduct in rodents treated with N-nitrosopyrrolidine. 201 22

The time courses of induction of liver cytosolic aldehyde dehydrogenases using benzaldehyde and propionaldehyde as substrates and NADP and NAD as co-factors after i.p. and intragastric (i.g.) administration of 2-acetylaminofluorene (2-AAF), 20-methylcholanthrene (20-MC), beta-naphthoflavone (beta-NF) and benzo[alpha]pyrene (B[alpha]P) were investigated in male Wistar rats. 2-AAF did not induce the aldehyde dehydrogenase activities with any substrate:co-factor combination. The other three inducers all induced the oxidation of the aldehydes in a reversible manner. With an i.p. route of administration (one daily dose for four consecutive days) (20-MC) was the most potent inducer giving a 240-fold increase of benzaldehyde: NADP activity on the ninth day. beta-NF elevated the activity 20-fold with peak activity at day 7, while B[alpha]P gave maximal induction on day 5 with a 60-fold increase in activity over the corresponding value for normal liver. The i.g. administration resulted in a weaker but coordinated induction of activity with peak activity on the sixth day for the different inducers. The activity ratio benzaldehyde:NADP/propionaldehyde:NAD, 0.78 in normal rats, was altered in all induced states to a level close to 4. The interpretation of our work supports the hypothesis that the inducers in this respect use the same mechanisms of induction. The differences noted can be explained by variations in the exposure of the liver to the administered dose and/or by differences in receptor affinity. The inducibility of benzaldehyde:NADP aldehyde dehydrogenase in rat liver exceeds by orders of magnitude the ability of the same inducers to increase the amount of the activity of other drug metabolizing enzymes such as glutathione S-transferase, cytochrome P450 and cytochrome b5. The reversible, drug-dependent induction characterized in normal rat liver in this work differs entirely from the persistent constitutive elevation of the same enzymes in preneoplastic liver nodules.
Carcinogenesis 1991 May
PMID:Kinetics of induction of cytosolic benzaldehyde: NADP and propionaldehyde: NAD aldehyde dehydrogenase activities in rat livers from male Wistar rats. 202 38

This communication describes a method and results for the immunohistochemical detection of a tumour-associated isoenzyme of aldehyde dehydrogenase (BALDH). The method is a substantial improvement over standard histochemical detection methods which require either frozen or mildly fixed tissues, since BALDH expression was detected in the cells of formalin-fixed paraffin-embedded liver tissues of both mice and rats. Using the immunohistochemical method, we detected BALDH expression diethylnitrosamine-induced hepatomas in the male Sprague-Dawley rat and in male B6C3F1 mouse hepatomas induced with either diethylnitrosamine, ethylnitrosourea or dichloroacetic acid. BALDH was also detected in three hepatoma cell culture lines which express different levels of BALDH. These results were compared to results with normal liver and hepatoma sections from the same animals and the three cell culture lines using a standard histochemical method to detect BALDH. In nearly all these tissue sections and cell cultures, expression of BALDH was detected in identical sites with either method. The diethylnitrosamine and dichloroacetic acid induction of the BALDH isozyme, as reported here, has not been reported previously and further substantiates the use of BALDH as a histochemical marker for mouse hepatocarcinogenesis. Given the few reliable histochemical markers for mouse hepatocarcinogenesis, the immunohistochemical method will be useful for further validation of BALDH as a histochemical marker for this species. Thus, BALDH expression could be detected in any number of carcinogen-induced lesions such as altered foci, nodule or hepatomas, from archived, formalin-fixed tissues of past mouse carcinogenesis studies which were based on a variety of mouse strains, carcinogens and induction protocols.
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PMID:Immunohistochemical detection of tumour-associated aldehyde dehydrogenase in formalin-fixed rat and mouse normal liver and hepatomas. 228 93

The effects of certain in vivo inducers of tumor-associated aldehyde dehydrogenase (aldehyde:NAD+ oxidoreductase, EC 1.2.1.3; ALDH) activity on the expression of tumor-associated ALDH (T-ALDH) in vitro have been investigated using cultured rat hepatocytes and hepatoma cell lines. Two distinct groups of T-ALDH inducers have been identified. Three hepatocarcinogenic initiators 2-acetylaminofluorene, diethylnitrosamine and ethionine, which cause changes in T-ALDH in vivo, do not induce T-ALDH activity in cultured rat hepatocytes or hepatoma cell lines following either short-term or long-term exposures. In contrast, polycyclic aromatic hydrocarbons, such as 3-methylcholanthrene, benzo[a]pyrene and 7,12-dimethylbenz[a]anthracene, induce an immediate increase of T-ALDH activity in both cultured rat hepatocytes and hepatoma cell lines. Synthesis and degradation rates of T-ALDH mRNA and protein have also been determined. The synthesis of T-ALDH protein is coupled with the increased synthesis of T-ALDH mRNA when the T-ALDH gene is constitutively expressed or activated by an inducer. Both T-ALDH mRNA (t1/2 = 25 - 34 h) and protein (t1/2 = 88 - 95 h) in high T-ALDH activity cell lines or low-activity cell lines treated with an inducer are relatively stable. Combined with previous studies, the results suggest that at least two different mechanisms are involved in T-ALDH gene expression; events occurring during initiation as well as during promotion appear to be involved in the genetically stable changes in T-ALDH gene expression which occur in vivo. The results also indicate that the lack of T-ALDH activity in normal hepatocytes or low-activity hepatoma cell lines is due to repression of the T-ALDH gene rather than to the differential stability of T-ALDH mRNA or protein.
Carcinogenesis 1990 Jul
PMID:Effects of hepatocarcinogenic initiators on aldehyde dehydrogenase gene expression in cultured rat hepatic cells. 237 65

In some chemically-induced hepatomas and in cultured transformed cells the aldehyde dehydrogenase activity was found increased in the presence of aromatic aldehyde as substrate. We studied this enzyme during diethyl-nitrosamine carcinogenesis in rat liver by using an aliphatic aldehyde, 4-hydroxynonenal, as substrate. 4-Hydroxynonenal is an important product of lipid peroxidation. The NAD- and NADP-dependent aldehyde dehydrogenase of the cytosolic fraction and the NADP-dependent aldehyde dehydrogenase of the microsomes show higher values in nodules and hepatoma than in normal liver. These results suggest that increased aldehyde dehydrogenase, when 4-hydroxynonenal is used, can be considered a marker of the neoplastic process, in the same way as the level of aldehyde dehydrogenase increased in presence of aromatic aldehyde.
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PMID:Oxidative metabolism of 4-hydroxy-2,3-nonenal during diethyl-nitrosamine-induced carcinogenesis in rat liver. 273 11

We have reported that normal rat urinary bladder possesses significant amounts of an aldehyde dehydrogenase (class 3 ALDH) expressed during hepatocarcinogenesis, but not detectable in normal liver. Changes in expression of both liver and bladder ALDH during N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN)-induced bladder carcinogenesis were studied. The ALDH phenotype was determined at intervals over 42 weeks by histochemical analysis, total ALDH activity assays and gel electrophoresis using propionaldehyde and NAD (P-NAD) which characterizes class 1 and 2 ALDH, or benzaldehyde and NADP (B-NADP) to determine class 3 ALDH. By total activity assays and gel electrophoresis, there was a significant decrease in bladder class 3 ALDH activity during weeks 5-15. Histochemical analysis clearly demonstrates changes in ALDH early in neoplastic development. Intense staining with B-NADP in regions of hyperplasia was first detectable at week 10. Staining in hyperplastic regions was accompanied by a significant decrease in ADLH in neighboring, apparently normal urothelium. As the urothelium became more abnormal, class 3 ALDH activity increased. By week 25, the bladder class 3 ALDH activity of BBN-treated animals was 2 times greater than the control group class 3 ALDH activity. Histochemically, all papillomas and carcinomas examined possessed class 3 ALDH. However, staining was heterogeneous within the lesions. Bladder neoplasm class 3 ALDH specific activity was greater than control group class 3 ALDH activity in 70% of papillomas and carcinomas. These results suggest events may be occurring in bladder similar to those in liver which alter expression of aldehyde dehydrogenase during carcinogenesis.
Carcinogenesis 1989 Nov
PMID:Changes in aldehyde dehydrogenase during rat urinary bladder carcinogenesis. 280 29

The metabolism of N-butyl-N-(3-formylpropyl)nitrosamine, a presumptive intermediate metabolite of the urinary bladder carcinogen N-butyl-N-(4-hydroxybutyl)nitrosamine, by rat liver has been examined. N-Butyl-N-(3-formylpropyl)nitrosamine was metabolized by an NADH-dependent reduction to N-butyl-N-(4-hydroxybutyl)nitrosamine and by an NAD+-dependent oxidation to N-butyl-N-(3-carboxypropyl)nitrosamine. The reduction of N-butyl-N-(3-formylpropyl)nitrosamine was inhibited by pyrazole. The oxidation of N-butyl-N-(3-formylpropyl)nitrosamine was studied further. The rate of oxidation in total rat liver was 3 mumol/min/g liver or 21 nmol/min/mg protein and was similar to that found for the oxidation of propionaldehyde, a model substrate for isozymes of rat liver aldehyde dehydrogenase. The rate of oxidation of N-butyl-N-(3-formylpropyl)nitrosamine by isozymes in rat liver cytosol was 2-2.5 times that found for propionaldehyde. The apparent Km for the NAD+-dependent oxidation of N-butyl-N-(3-formylpropyl)nitrosamine was 20-30 microM, which is considerably lower than values reported for known substrates of aldehyde dehydrogenase. The NAD+-dependent oxidation of N-butyl-N-(3-formylpropyl)nitrosamine was inhibited 40-50% by 50 microM disulfiram, 60-70% by 100 microM disulfiram, and 50% by 0.4 mM sodium arsenite. These studies show that N-butyl-N-(3-formylpropyl)nitrosamine is very rapidly oxidized to N-butyl-N-(3-carboxypropyl)nitrosamine in rat liver by aldehyde dehydrogenase and the results may help to explain why the 3-formylpropyl intermediate has not been directly identified as a metabolite of N-butyl-N-(4-hydroxybutyl)nitrosamine in urine or in isolated hepatocytes.
Carcinogenesis 1988 Nov
PMID:Oxidation of N-butyl-N-(3-formylpropyl)nitrosamine to N-butyl-N-(3-carboxypropyl)nitrosamine in rat liver and inhibition by disulfiram. 318 Mar 45

Diethylnitrosamine following partial hepatectomy followed by phenobarbital promotion was used to study changes in aldehyde dehydrogenase (ALDH) activity during rat hepatocarcinogenesis. Over a period of 350 days, animals were killed at intervals and the ALDH phenotype of normal liver and any lesions was characterized by histochemical analysis, total activity assays and gel electrophoresis using propionaldehyde and NAD+ to detect normal liver ALDH activities, and benzaldehyde and NADP+ for tumor-associated ALDH. In contrast to previously tested protocols, no significant changes in ALDH activity were demonstrable by histochemistry or total activity assays in preneoplastic livers. However, nine of 16 (56%) of the hepatocellular carcinomas examined expressed the tumor-associated ALDH phenotype. The present results are integrated with previous observations as a hypothesis explaining the roles of initiation and promotion in expression of the tumor-associated aldehyde dehydrogenase phenotype.
Carcinogenesis 1987 Jun
PMID:Changes in aldehyde dehydrogenase activity during diethylnitrosamine-initiated rat hepatocarcinogenesis. 360 75


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