Isotope effects and their implications for the covalent binding of inhaled (/sup 3/H)- and (/sup 14/C)formaldehyde in the rat nasal mucosa

Journal Article · Mon Jun 15 04:00:00 EDT 1987 · Toxicol. Appl. Pharmacol.; (United States)

DOI:https://doi.org/10.1016/0041-008X(87)90182-7· OSTI ID:6470648

Hd', Heck; Casanova, M

DNA-protein crosslinks were formed in the nasal respiratory mucosa of Fischer-344 rats exposed for 3 hr to selected concentrations of (/sup 3/H)- and (/sup 14/C)formaldehyde (/sup 3/HCHO and H/sup 14/CHO). In rats depleted of glutathione (GSH) and exposed to 10 ppm of /sup 3/HCHO and H/sup 14/CHO, the /sup 3/H//sup 14/C ratio of the fraction of the DNA that was crosslinked to proteins was significantly (39 +/- 6%) higher than that of the inhaled gas. This suggests an isotope effect, either on the formation of DNA-protein crosslinks by labeled HCHO or on the oxidation of labeled HCHO catalyzed by formaldehyde (FDH) or aldehyde dehydrogenase (AldDH). The possibility of an isotope effect on the formation of crosslinks was investigated using rat hepatic nuclei incubated with (/sup 3/H)- and (/sup 14/C)formaldehyde (0.1 mM, 37 degrees C). A small (3.4 +/- 0.9%) isotope effect was detected on this reaction, which slightly favored /sup 3/HCHO over H/sup 14/CHO in binding to DNA. The magnitude of this isotope effect cannot account for the high isotope ratio observed in the crosslinked DNA in vivo. The possibility of an isotope effect on the oxidation of /sup 3/HCHO and H/sup 14/CHO catalyzed by FDH was investigated using homogenates of the rat nasal mucosa incubated with (/sup 3/H)- and (/sup 14/C)formaldehyde at total formaldehyde concentrations ranging from 0.1 to 11 microM, NAD+ (1 mM), GSH (15 mM), and pyrazole (1 mM). The experiments showed that /sup 3/HCHO is oxidized significantly more slowly than H/sup 14/CHO under these conditions (Vmax/Km (H/sup 14/CHO) divided by Vmax/Km (/sup 3/HCHO) = 1.82 +/- 0.11). A similar isotope effect was observed in the absence of GSH, presumably due to the oxidation of /sup 3/HCHO and H/sup 14/CHO catalyzed by AldDH.

• Research Organization: Chemical Industry Institute of Toxicology, Research Triangle Park, NC
• OSTI ID: 6470648
• Journal Information: Toxicol. Appl. Pharmacol.; (United States), Journal Name: Toxicol. Appl. Pharmacol.; (United States) Vol. 1; ISSN TXAPA
• Country of Publication: United States
• Language: English

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560300* -- Chemicals Metabolism & Toxicology
59 BASIC BIOLOGICAL SCIENCES
63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.
ADDUCTS
ALDEHYDES
ANIMALS
BIOCHEMICAL REACTION KINETICS
BOROHYDRIDES
BORON COMPOUNDS
CARBON 14 COMPOUNDS
CHEMICAL REACTIONS
CROSS-LINKING
DNA
DNA ADDUCTS
DOSE-RESPONSE RELATIONSHIPS
ENZYME ACTIVITY
ENZYMES
FORMALDEHYDE
HYDROGEN COMPOUNDS
INHALATION
INTAKE
ISOTOPE APPLICATIONS
ISOTOPE EFFECTS
KINETICS
LABELLED COMPOUNDS
MAMMALS
MEMBRANES
METABOLISM
MUCOUS MEMBRANES
NUCLEIC ACIDS
ORGANIC COMPOUNDS
OXIDOREDUCTASES
POLYMERIZATION
PROTEINS
RATS
REACTION KINETICS
RESPIRATORY SYSTEM
RODENTS
TRACER TECHNIQUES
TRITIUM COMPOUNDS
VERTEBRATES