Catalase mediates acetaldehyde formation from ethanol in fetal and neonatal rat brain.
Fetal ethanol (E) exposure has well documented deleterious effects on brain development, yet it is uncertain if the neurotoxicity of maternal E consumption is generated by E itself, by its primary metabolite acetaldehyde (AcHO), or both. The current studies present evidence that homogenates of immature rat brains can generate AcHO via a catalase (CAT)-mediated reaction and that AcHO may be produced in vivo by this system. Homogenates of day 19 fetal rat brain were incubated with E (50 mM). When incubated with CAT inhibitors (sodium azide or 3-aminotriazole), AcHO formation was blocked, whereas neither the alcohol dehydrogenase inhibitor, 4-methylpyrazole, nor P-450 inhibitors decreased AcHO production. Three hours after one oral dose of E (4 g/kg) to a pregnant dam (gestation day 19), AcHO levels in fetal brain increased to 14.28 +/- 1.82 nM/g tissue. Baseline CAT activity in day 19 fetal brains was 4.5 times adult values (p < 0.05). Western blot analysis determined that CAT protein level in the day 19 fetal brain exceeded that in adult brain by 2.5 times. One hour after a single dose of E, CAT activity in day 19 fetal brain increased by 8.2 units/mg protein. In 5-day-old neonatal brains during the "third trimester" brain growth spurt, baseline CAT activity was twice the adult values (p < 0.05) and a 2-day in vivo E regimen increased AcHO levels to four times the control values, with a concomitant 1.7-fold increase in CAT activity. This was prevented by administration of a CAT inhibitor (3-amino-1,2,4-triazole). Immunohistochemical staining of neonatal brains exposed to E illustrated the presence of acetaldehyde-protein adducts. We conclude that AcHO is likely produced in rat fetal and neonatal brain via CAT-mediated oxidation of E. This phenomenon may be an important factor in the neurotoxic effects of in utero E exposure.
Hamby-Mason
R
R
Department of Medicine, University of Texas Health Science Center at San Antonio 78284-7878, USA.
Chen
J J
JJ
Schenker
S
S
Perez
A
A
Henderson
G I
GI
D000079:Acetaldehyde / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000196:embryology* / Q000201:enzymology; D002374:Catalase / Q000502:physiology*; D000431:Ethanol / Q000493:pharmacokinetics* / Q000633:toxicity; D005260:Female; D063647:Fetal Alcohol Spectrum Disorders / Q000196:embryology* / Q000201:enzymology; D005865:Gestational Age; D007124:Immunoenzyme Techniques; D008297:Male; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley
D000431:Ethanol; D002374:Catalase; D000079:Acetaldehyde