The effect of inhibition of aldehyde dehydrogenase on nasal uptake of inspired acetaldehyde.
At exposure concentrations of 750 ppm or more, acetaldehyde is a rodent inhalation carcinogen that induces nasal tumors. Aldehyde dehydrogenase (ALDH) is thought to be an important detoxifying enzyme for aldehydes. Although nasal tissues express ALDH, the importance of this enzyme relative to delivered dosage rates at high-inspired concentrations is not well defined. To provide such information, uptake of inspired acetaldehyde was measured at an inspiratory flow rate that approximated the minute ventilation rate in the surgically isolated nasal cavity of F 344 rats pretreated with either saline (control) or the ALDH inhibitor, cyanamide (10 mg/kg s.c.). ALDH activities (substrate concentration 3 times the K(m)) in anterior (respiratory mucosa) and posterior (olfactory mucosa) nasal tissues averaged 160 and 210 nmol/min), respectively, in control animals (total activity 370 nmol/min), compared to 60 and 80 nmol/min, respectively, in cyanamide-pretreated rats (p < 0.05), indicating that approximately 60% inhibition was obtained. Nasal uptake was measured at 3 inspired concentrations: 10, 300, and 1500 ppm. At these concentrations, acetaldehyde uptake efficiency averaged 54, 37, and 34% in saline-pretreated rats, respectively (p < 0.05). In absolute terms, the delivered dosage rates at these exposure concentrations averaged 21, 420, and 1990 nmol/min. The concentration dependence on uptake suggests a saturable process was involved. At inspired concentrations of 300 ppm or more, the delivered dosage rates exceeded the measured specific activity for nasal ALDH of 370 nmol/min. Cyanamide pretreatment abolished the concentration dependence. Specifically, uptake efficiencies in cyanamide-pretreated rats averaged 30, 27, and 31% at inspired concentrations of 10, 300, and 1500 ppm, respectively (p > 0.05); delivered dosage rates were 12, 310, and 1780 nmol/min. Thus, cyanamide pretreatment reduced nasal-delivered dosage rates at inspired concentrations of 10, 300, and 1500 ppm, respectively by 9, 110, and 210 nmol/min, values that correspond well with the total nasal ALDH activity of 370 nmol/min. In toto, these results suggest that inspired acetaldehyde is metabolized in situ by ALDH, but at exposure concentrations of 300 ppm or greater, the delivered dosage rate may equal or exceed the capacity of this enzyme.
Stanek
J J
JJ
University of Connecticut, Storrs 06269-2092, USA.
Morris
J B
JB
D000079:Acetaldehyde / Q000032:analysis / Q000493:pharmacokinetics*; D000280:Administration, Inhalation; D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors*; D000818:Animals; D002273:Carcinogens / Q000493:pharmacokinetics*; D003432:Cross-Linking Reagents; D003484:Cyanamide / Q000494:pharmacology*; D004247:DNA / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D009297:Nasal Mucosa / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D009666:Nose / Q000601:surgery; D011506:Proteins / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D013047:Specific Pathogen-Free Organisms; D013997:Time Factors
D002273:Carcinogens; D003432:Cross-Linking Reagents; D011506:Proteins; D003484:Cyanamide; D004247:DNA; D000444:Aldehyde Dehydrogenase; D000079:Acetaldehyde