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PubMed1989

In vivo enzymology: a deuterium NMR study of formaldehyde dismutase in Pseudomonas putida F61a and Staphylococcus aureus.

High-resolution deuterium NMR spectroscopy has been used to follow the detoxifying metabolism of [D2]formaldehyde in vivo in several bacterial species. Production of [D2]methanol in Escherichia coli confirms that the oxidation and reduction pathways of metabolism are independent in this organism. Efficient production of equimolar quantities of [D]formate and [D3]methanol in Pseudomonas putida F61a and Staphylococcus aureus implicates a formaldehyde dismutase, or "cannizzarase", activity. These observations imply that the unusual formaldehyde resistance in P. putida F61a is a direct result of efficient dismutation acting as a route for detoxification. Cross-dismutation experiments yield an enzymic kinetic isotope effect of ca. 4 for H vs D transfer and a similar spectrum of substrate specificity to the isolated enzyme. [D]benzyl alcohol produced by cross-dismutation of [D2]formaldehyde and benzaldehyde in P. putida is demonstrated to have the R configuration by a novel deuterium NMR assay. Additionally, S. aureus produces methyl formate as a product of formaldehyde detoxification, apparently by oxidizing the methanol hemiacetal of formaldehyde.

Alcohol Oxidoreductases↗

PubMed2000

Kinetic mechanism of human glutathione-dependent formaldehyde dehydrogenase.

Formaldehyde, a major industrial chemical, is classified as a carcinogen because of its high reactivity with DNA. It is inactivated by oxidative metabolism to formate in humans by glutathione-dependent formaldehyde dehydrogenase. This NAD(+)-dependent enzyme belongs to the family of zinc-dependent alcohol dehydrogenases with 40 kDa subunits and is also called ADH3 or chi-ADH. The first step in the reaction involves the nonenzymatic formation of the S-(hydroxymethyl)glutathione adduct from formaldehyde and glutathione. When formaldehyde concentrations exceed that of glutathione, nonoxidizable adducts can be formed in vitro. The S-(hydroxymethyl)glutathione adduct will be predominant in vivo, since circulating glutathione concentrations are reported to be 50 times that of formaldehyde in humans. Initial velocity, product inhibition, dead-end inhibition, and equilibrium binding studies indicate that the catalytic mechanism for oxidation of S-(hydroxymethyl)glutathione and 12-hydroxydodecanoic acid (12-HDDA) with NAD(+) is random bi-bi. Formation of an E.NADH.12-HDDA abortive complex was evident from equilibrium binding studies, but no substrate inhibition was seen with 12-HDDA. 12-Oxododecanoic acid (12-ODDA) exhibited substrate inhibition, which is consistent with a preferred pathway for substrate addition in the reductive reaction and formation of an abortive E.NAD(+).12-ODDA complex. The random mechanism is consistent with the published three-dimensional structure of the formaldehyde dehydrogenase.NAD(+) complex, which exhibits a unique semi-open coenzyme-catalytic domain conformation where substrates can bind or dissociate in any order.

Aldehyde Oxidoreductases↗

PubMed1976

Purification and properties of formaldehyde dehydrogenase and formate dehydrogenase from Candida boidinii.

Formaldehyde hydrogenase and formate dehydrogenase were purified 130-fold and 19-fold respectively from Candida boidinii grown on methanol. The final enzyme preparations were homogenous as judged by acrylamide gel electrophoresis and by sedimentation in an ultracentrifuge. The molecular weights of the enzymes were determined by sedimentation equilibrium studies and calculated as 80000 and 74000 respectively. Dissociation into subunits was observed by treatment with sodium dodecylsulfate. The molecular weights of the polypeptide chains were estimated to be 40000 and 36000 respectively. The NAD-linked formaldehyde dehydrogenase specifically requires reduced glutathione for activity. Besides formaldehyde only methylglyoxal served as a substrate but no other aldehyde tested. The Km values were found to be 0.25 mM for formaldehyde, 1.2 mM for methylglyoxal, 0.09 mM for NAD and 0.13 mM for glutathione. Evidence is presented which demonstrates that the reaction product of the formaldehyde-dehydrogenase-catalyzed oxidation of formaldehyde is S-formylglutathione rather than formate. The NAD-linked formate dehydrogenase catalyzes specifically the oxidation of formate to carbon dioxide. The Km values were found to be 13 mM for formate and 0.09 mM for NAD.

Aldehyde Oxidoreductases↗

PubMed1992

NAD-linked, factor-dependent formaldehyde dehydrogenase or trimeric, zinc-containing, long-chain alcohol dehydrogenase from Amycolatopsis methanolica.

NAD-linked, factor-dependent formaldehyde dehydrogenase (FD-FA1DH) of the Gram-positive methylotrophic bacterium, Amycolatopsis methanolica, was purified to homogeneity. It is a trimeric enzyme with identical subunits (molecular mass 40 kDa) containing 6 atoms Zn/enzyme molecule. The factor is a heat-stable, low-molecular-mass compound, which showed retention on an Aminex HPX-87H column. Inactivation of the factor occurred during manipulation, but activity could be restored by incubation with dithiothreitol. The identity of the factor is still unknown. It could not be replaced by thiol compounds or cofactors known to be involved in metabolism of C1 compounds. Of the aldehydes tested, only formaldehyde was a substrate. However, the enzyme showed also activity with higher aliphatic alcohols and the presence of the factor was not required for this reaction. Methanol was not a substrate, but high concentrations of it could replace the factor in the conversion of formaldehyde. Presumably, a hemiacetal of formaldehyde is the genuine substrate, which, in the case of methanol, acts as a factor leading to methylformate as the product. This view is supported by the fact that formate could only be detected in the reaction mixture after acidification. Inhibition studies revealed that the enzyme contains a reactive thiol group, being protected by the binding of NAD against attack by heavy-metal ions and aldehydes. Studies on the effect of the order of addition of coenzyme and substrate suggested that optimal catalysis required NAD as the first binding component. Substrate specificity and the induction pattern clearly indicate a role of the enzyme in formaldehyde oxidation. However, since FD-FA1DH was also found in A. methanolica grown on n-butanol, but not on ethanol, it may have a role in the oxidation of higher aliphatic alcohols as well. FD-FA1DH and the factor from A. methanolica are very similar to a combination already described for Rhodococcus erythropolis [Eggeling, L. & Sahm, H. (1985) Eur. J. Biochem. 150, 129-134]. NAD-linked, glutathione-dependent formaldehyde dehydrogenase (GD-FA1DH) resembles FD-FA1DH in many respects. Since glutathione has so far not been detected in Gram-positive bacteria, FD-FA1DH could be the counterpart of this enzyme in Gram-positive bacteria. Alignment of the N-terminal sequence (31 residues) of FD-FA1DH with that of GD-FA1DH from rat liver indeed showed similarity (30% identical positions). However, comparable similarity was found with class I alcohol dehydrogenase from this organism and with cytosolic alcohol dehydrogenase from Saccharomyces cerevisiae, isozyme 1.(ABSTRACT TRUNCATED AT 400 WORDS)

Actinomycetales↗

PubMed1994

Sequence of the gene for a NAD(P)-dependent formaldehyde dehydrogenase (class III alcohol dehydrogenase) from a marine methanotroph Methylobacter marinus A45.

A fragment of Methylobacter marinus A45 DNA has been cloned and sequenced, and an open reading frame has been identified that could code for a 46-kDa polypeptide. Comparison of the deduced amino acid sequence of the polypeptide against the protein data bank has revealed strong similarity with a number of alcohol dehydrogenases, with highest similarity towards class III alcohol dehydrogenases, which recently have been shown to be identical to glutathione-dependent formaldehyde dehydrogenases. We were unable to measure appreciable levels of NAD(P)-dependent formaldehyde dehydrogenases or alcohol dehydrogenase activities using aldehydes or primary or secondary alcohols in cell-free extracts from batch cultures of M. marinus A45. However, formaldehyde dehydrogenases activity was detected on zymograms. Our data suggest that, although NAD(P)-linked formaldehyde dehydrogenase or alcohol dehydrogenase activities are undetectable in cell-free extracts of most methylotrophs employing the ribulose monophosphate pathway for formaldehyde assimilation and dissimilation, the gene encoding formaldehyde dehydrogenase is present in M. marinus A45 and may be present in more of these organisms as well.

Aldehyde Oxidoreductases↗

PubMed2005

Flow injection determination of formaldehyde by its catalytic effect on the oxidation of sulfonazo III by bromate with spectrophotometric detection.

A simple and sensitive flow injection method with spectrophotometric detection was developed for the determination of formaldehyde. The method is based on the catalytic effect of formaldehyde on the oxidation of sulfonazo III with bromate in acidic media. The decrease in absorbance of the reaction mixture was measured at 566 nm. The calibration graph was linear in the range of 0.005 to 2.80 microg ml(-1) formaldehyde at a rate of 38 +/- 4 samples h(-1). The limit of detection was 4 ng ml(-1). The relative standard deviations for ten replicate measurements of 0.20, 0.50 and 1.00 microg ml(-1) formaldehyde were 1.3, 0.8 and 0.7%, respectively. The method was applied to the determination of formaldehyde in river water, shampoo and melamine-formaldehyde resin.

Journal Article↗

PubMed1986

Substrate specificity of bovine liver formaldehyde dehydrogenase.

Formaldehyde dehydrogenases isolated from several different biological sources have been reported to catalyze the NAD+-dependent oxidative acylation of glutathione by methylglyoxal to form S-pyruvylglutathione, suggesting the involvement of this enzyme in the metabolism of methylglyoxal. However, formaldehyde dehydrogenase from bovine liver is found not to use methylglyoxal or related alpha-ketoaldehydes as substrates. Using methylglyoxal with the enzyme under conditions favoring the forward reaction did not result in the formation of S-pyruvylglutathione. Using independently synthesized S-pyruvylglutathione with the enzyme under conditions favoring the reverse reaction did not result in the production of methylglyoxal. In addition, methylglyoxal and several related alpha-ketoaldehydes did not exhibit detectable activity with formaldehyde dehydrogenase partially purified from human liver, contrary to a previous report. Some, if not all, past reports that methylglyoxal serves as a substrate for the dehydrogenase may be due to the demonstrated presence of contaminating formaldehyde in some commercially available preparations of methylglyoxal. In a related study, S-hydroxymethylglutathione, formed by pre-equilibrium addition of formaldehyde to glutathione, is concluded to be direct substrate for the dehydrogenase. This follows from the observation that the catalytic turnover number of the enzyme in the forward direction exceeds by a factor of approximately 20 the first order rate constant for decomposition of S-hydroxymethylglutathione to glutathione and formaldehyde (k = 5.03 +/- 0.30 min-1, pH 8, 25 degrees C).

Acylation↗

PubMed1999

Analysis of formaldehyde in the headspace of urine from bladder and prostate cancer patients using selected ion flow tube mass spectrometry.

We have used selected ion flow tube mass spectrometry (SIFT-MS) to determine the concentration of formaldehyde in the headspace of urine from patients suffering from bladder and prostate cancer and from several healthy subjects as controls. We address the potential problems associated with the use of ion chemistry to quantify formaldehyde in the presence of the relatively large number densities of water molecules and show that formaldehyde can be quantified in urine headspace using analysis by SIFT-MS. These studies show that formaldehyde is clearly elevated in the headspace of the urine from the cancer patients as compared with urine from the healthy controls. Thus, with further improvements in the methodology and the sensitivity of our SIFT-MS technique, formaldehyde quantification in urine headspace using this new analytical method could be a valuable non-invasive indicator of the presence of early-stage tumours in the body.

Formaldehyde↗

PubMed1999

Reduced fertility among female wood workers exposed to formaldehyde.

BACKGROUND: The aim of the study was to investigate whether exposure to formaldehyde, organic solvents or other chemicals in the wood-processing industry affects the fertility of women. METHODS: For this purpose, a retrospective study on time to pregnancy was conducted among female wood workers who had given birth during 1985-1995. Data on pregnancy history, time to pregnancy, occupational exposures, and potential confounders were collected by a questionnaire; 64% (699/1,094) participated. The exposure assessment was conducted by an occupational hygienist. The data on time to pregnancy were analyzed with the discrete proportional hazards regression. RESULTS: Exposure to formaldehyde was significantly associated with delayed conception: adjusted fecundability density ratio, FDR, was 0.64 (95% CI 0.43-0.92). At high exposure if no gloves were used, the FDR was 0.51 (% CI 0.28-0.92). Exposure to phenols, dusts, wood dusts, or organic solvents was not related to the time to pregnancy. Additionally, an association was observed between exposure to formaldehyde and an increased risk of spontaneous abortion (concerning previous spontaneous abortions, reported by the women). Associations between exposure to formaldehyde or to organic solvents and endometriosis, and between exposure to organic solvents or to dusts and salpingo-oophoritis were also suggested. CONCLUSIONS: The study suggests that a woman's occupational exposure to formaldehyde has an adverse effect on fertility.

Adult↗

PubMed1987

Exposure to formaldehyde in anatomy: an occupational health hazard?

The adverse effects of formaldehyde have been discussed very emotionally in public. Anatomists, technicians in histology and embalming laboratories, as well as medical students during their dissection course are all exposed to formaldehyde, which in many situations crosses the threshold for irritation of the eyes and upper respiratory tract. There is no doubt about the acute toxic effects and the occurrence of contact dermatitis caused by formaldehyde. Studies in rats and mice using high concentrations over an extremely long period (which would not be tolerated by humans) resulted in squamous carcinoma of the nose. Epidemiologic studies on the mortality of medical personnel exposed to formaldehyde do not provide sufficient evidence of cancerogenicity. A number of recommendations will be given for defining the exact concentration in a dissecting room or laboratory and for ways of reducing formaldehyde concentrations and thus minimizing adverse health hazards. These data could initiate a discussion among anatomists, and with technicians and students, based on a sound scientific background rather than on emotion.

Anatomy↗

PubMedDate not supplied

Simultaneous determination of methenamine and formaldehyde in the urine of humans after methenamine administration.

Methenamine (hexamethylenetetramine) and its hydrolysis product formaldehyde are determined in the presence of each other in urine by a spectrophotometric method. Formaldehyde is assayed by a colour reaction with tryptophan, sulphuric acid and ferric chloride after precipitating methenamine by three treatments with mercuric chloride. Methenamine is indirectly analysed by hydrolysis to formaldehyde with dilute hydrochloric acid. Formaldehyde levels as low as 5.0 micrograms ml-1 in the presence of methenamine concentrations as high as 2.5 mg ml-1 can be assayed. Of practical significance is the feature that urine may be stored up to 1 weeks for analysis, by appropriate dilution and freezing, without excessive loss of methenamine or formaldehyde. The method was applied to the dtermination of the bioavailability of methenamine hippurate in ten human volunteers.

Biological Availability↗

PubMed1983

Synergism in the transformation of hamster embryo cells treated with formaldehyde and adenovirus.

Formaldehyde is a large production volume chemical widely distributed in research laboratories, industrial workplaces, and home and personal environments. Inhalation studies with formaldehyde have documented its ability to produce squamous cell carcinomas in rats. When primary hamster embryo cells were treated by gaseous exposure to formaldehyde or by incorporation into the medium, a dose-related increase in the frequency of SA7 virus transformation was produced. The length of chemical treatment and the time interval before subsequent addition of transforming virus was critical, with two-hr treatment times as the most efficient. Treatment by gaseous exposure permitted utilization of lower treatment concentrations. Determination of formaldehyde concentrations in culture media of bioassay dishes treated by this method documented that 2.2 micrograms/ml produced significantly enhanced viral transformation. Exposure of hamster embryo cells to formaldehyde by these methods produces reproducible and quantitative genotoxic effects.

Adenoviridae↗

PubMed1986

Formaldehyde and cancers of the pharynx, sinus and nasal cavity: I. Occupational exposures.

A population-based case-control study was undertaken in 13 counties of western Washington to determine if occupational formaldehyde exposure was related to cancer of the oro- and hypopharynx (OHPC, N = 205), nasopharynx (NPC, N = 27) or sinus and nasal cavity (SNC, N = 53). Controls were selected by random digit dialing (N = 552). A telephone interview inquired about lifetime occupational history as well as a number of potential confounding factors, including smoking and drinking. Approximately half (N = 143) of the case interviews were with next-of-kin. Occupational formaldehyde exposures were assessed by application of job-exposure matrix developed for this study which classified unique job codes into 4 categories based on judgement of likelihood and intensity of formaldehyde exposure. Exposure scores were calculated by weighing the number of years in a formaldehyde-associated job by the assigned exposure level. The effects assuming a 15-year induction period were also investigated. Logistic regression was used to estimate exposure odds ratios (OR) while taking into account multiple risk factors for each site. No significant associations were found between occupational formaldehyde exposure and any of the cancer sites under study. However, relative risk estimates associated with the highest exposure score categories were elevated for OHPC (OR = 1.3, 95% Confidence Interval = 0.6-3.1) and NPC (OR = 2.1, 95% CI = 0.4-10.0) when an induction period was accounted for. When only live interviews were considered, the odds ratios for OHPC and NPC increased to 1.7 and 3.1 respectively. Several limitations in the study tend to conservatively bias the results and must be taken into account in its interpretation.

Adenocarcinoma↗

PubMed2005

Protective effect of NAC on formaldehyde-containing-ZOE-based root-canal-sealers-induced cyclooxygenase-2 expression and cytotoxicity in human osteoblastic cells.

Cyclooxygenase-2 (COX-2) is an inducible enzyme believed to be responsible for prostaglandin synthesis at site of inflammation. Recently, the activation of COX-2 expression may be one of the important pathogenesis of root-canal-sealers-induced periapical inflammation. However, little is known about whether chemical interaction can modulate the COX-2 expression and cytotoxicity induced by formaldehyde-containing-ZOE-based root canal sealers. The aim of this study was to investigate the effects of antioxidants such as catalase, superoxide dismutase (SOD), and N-acetyl-L-cysteine (NAC) on N2- and endomethasone-induced COX-2 mRNA gene and cytotoxicity in human osteoblastic cell line U2OS cells. Our data demonstrated that both formaldehyde-containing-ZOE-based root canal sealers were found to induce COX-2 mRNA gene expression in U2OS cells. The addition of glutathione (GSH) precursor NAC led to decrease the induction of COX-2 mRNA gene expression and cytotoxicity by both N2 and Endomethasone (p < 0.05). However, catalase and SOD lacked the ability to prevent cytotoxicity and COX-2 mRNA gene expression induced by N2 and Endomethasone (p > 0.05). The data presented here demonstrated that the activation of COX-2 mRNA gene expression may be one of the pathogenesis of formaldehyde-containing-ZOE-based root-canal-sealers-induced periapical inflammation. In addition, GSH depletion, but not the attack of oxygen free radicals, could be the mechanism for cytotoxicity and COX-2 mRNA gene expression induced by formaldehyde-containing-ZOE-based root canal sealers. NAC appears as a useful agent in protecting cell damage mediated by formaldehyde-containing-ZOE-based root canal sealers.

Acetylcysteine↗

PubMed1993

Pulmonary cytochrome P450 in rats exposed to formaldehyde vapor.

The lungs of rats exposed to formaldehyde vapor, for 6 hr/day over 4 consecutive days, were examined for signs of injury and for changes in the level, or activity, of cytochrome P450. The animals were supplied with 10 ppm formaldehyde vapor generated, in two separate experiments, either from an aqueous solution of formaldehyde or from heated paraformaldehyde. All rats were exposed for 6 hr, on each of 4 consecutive days, and killed 1 day after the onset of the fourth period of exposure. The lung weights and gains in body weight of exposed animals were indistinguishable from those of their controls. Lungs from the formaldehyde-exposed animals did not show any signs of injury, even at the ultrastructural level. Bronchoalveolar lavage samples from exposed animals showed no increase in alkaline phosphatase or gamma-glutamyl transpeptidase activity. The total concentration of cytochrome P450 in the lungs of exposed animals was similar to that found in their controls. The P450 activity of pulmonary microsomes from exposed animals was not significantly different from that obtained with samples from the control animals. These results indicate that repeated exposure to 10 ppm formaldehyde vapor does not injure the deep lung of rats and has no effect on the level of lung P450 or on its activity against substrates for the most common pulmonary forms of this enzyme.

Air Pollutants↗

PubMed1993

An experimental study of the organic molecules produced in cometary and interstellar ice analogs by thermal formaldehyde reactions.

Thermally promoted formaldehyde (H2CO) reactions in very low temperature ices have been studied to test their importance as a source of organic molecules in astrophysical environments such as comets and interstellar ices. The infrared absorption strengths of a number of the H2CO bands were measured in 10 K ices of pure H2CO and H20:H2CO = 100:3. Infrared spectroscopy was used to monitor the formaldehyde chemistry during warm-up of ices containing H2CO and one or more of the molecules H2O, CH3OH, CO, CO2, O2, and NH3. Formaldehyde reactions do not proceed at low temperatures in the absence of NH3. However, even small traces of NH3 (NH3/H2CO > or = 0.005) are sufficient to induce conversion of a considerable fraction (> 40%) of the H2CO into organic residues. Formaldehyde reactions were observed to start at temperatures as low as 40 K for NH3:H2CO binary ices and at approximately 80 K in astrophysically relevant (i.e., H2O-dominated) ices. A total of five different organic products of these reactions can be distinguished by infrared spectroscopy. One of them is polyoxymethylene (POM), a well-known H2CO polymerization product, whereas the others are reaction products of H2CO with H20, CH3OH and NH3. These all seem to be derivatives of polyoxymethylene. The nature of the components and their relative abundances depend strongly on the initial composition of the ice mixture as well as on the ice's irradiation history. We estimate that about 1% of the organics found in the coma of Comet Halley could have been produced by thermal formaldehyde reactions taking place in the nucleus.

Ammonia↗

PubMed2001

A review of adverse pregnancy outcomes and formaldehyde exposure in human and animal studies.

We examine the potential for reproductive and developmental effects from formaldehyde exposure. Formaldehyde is unlikely to reach the reproductive system in humans in concentrations sufficient to cause damage since it is rapidly metabolized and detoxified upon contact with the respiratory tract. While there are effects seen in in vitro studies or after injection, there is little evidence of reproductive or developmental toxicity in animal studies under exposure levels and routes relevant to humans. Most of the epidemiology studies examined spontaneous abortion and showed some evidence of increased risk (meta-relative risk=1.4, 95% CI 0.9-2.1). We found evidence of reporting biases and publication biases among the epidemiology studies and when these biases were taken into account, we found no evidence of increased risk of spontaneous abortion among workers exposed to formaldehyde (meta-relative risk=0.7, 95% CI 0.5-1.0). The small number of studies on birth defects, low birth weight, and infertility among formaldehyde workers; the limitations in the design of these studies; and the inconsistent findings across these studies make it difficult to draw conclusions from the epidemiology data alone. However, information from experimental studies and studies of metabolism indicate reproductive impacts are unlikely at formaldehyde exposures levels observed in the epidemiology studies.

Abnormalities, Drug-Induced↗

PubMed1995

Immunohistochemical localization of p53, PCNA, and TGF-alpha proteins in formaldehyde-induced rat nasal squamous cell carcinomas.

Mutation of the p53 tumor suppressor gene is a common event in many human cancers and has been specifically associated with invasive squamous cell carcinoma of the human skin and respiratory tract. Alterations in the p53 gene have also been identified in certain rodent tumors, including formaldehyde-induced nasal squamous cell carcinomas. Overexpression of transforming growth factor-alpha (TGF-alpha) is associated with carcinomas of the head and neck and respiratory tract in human patients and formaldehyde-induced rat nasal squamous cell carcinomas. Sections of rat noses containing tumors and other formaldehyde-induced lesions from rats exposed to 15 ppm formaldehyde vapor were examined using immunohistochemical techniques to detect and identify potential relationships between the presence and distribution of p53, proliferating cell nuclear antigen (PCNA), and TGF-alpha proteins. The five tumors that had p53 mutations were for mutant p53 protein by immunohistochemistry and three of six tumors with no detected p53 mutations were also immunoreactive for p53 protein. The presence, pattern, and distribution of p53 staining in tissue sections depended on the morphology of the lesion. PCNA immunoreactivity was strikingly similar in pattern and distribution to p53 immunoreactivity. The pattern and distribution of immunoreactivity for TGF-alpha did not directly correlate with the other markers. Mutation of the p53 tumor suppressor gene may be an important step in the progression of formaldehyde-induced nasal carcinogenesis in the rat. This study demonstrated that immunohistochemistry is a useful tool for the identification of sites within tumors that might have p53 mutations.

Animals↗