ABSTRACT
The interaction of Ro15-4513 (5 mg/kg) with ethanol (3 g/kg, 60%w/v bolus) in dogs was investigated. Ro15-4513 challenge 120 minutes after a single ethanol dose had no significant effect on blood ethanol concentration or heart rate. In the same experiment, (1) blood acetaldehyde concentration was elevated to more than double the control value (vehicle only, no Ro15-4513), and (2) systolic blood pressure decreased to less than 60% of control. Further investigation revealed: (1) after Ro15-4513, area under the blood acetaldehyde vs time curve was more than twofold greater (p = 0.0006) than control, and the area under the systolic blood pressure vs time curve was 76% (p = 0.0027) of control. Based on these results, we propose that an inter-relationship exists between Ro15-4513, blood acetaldehyde concentration, and systolic blood pressure in ethanol intoxicated dogs.
Subject(s)
Alcoholic Intoxication/metabolism , Azides/pharmacology , Benzodiazepines/pharmacology , Central Nervous System Depressants/pharmacokinetics , Ethanol/pharmacokinetics , Acetaldehyde/blood , Acetaldehyde/metabolism , Animals , Biotransformation , Blood Pressure/drug effects , Central Nervous System Depressants/blood , Dogs , Ethanol/blood , Heart Rate/drug effects , Heart Rate/physiology , Inactivation, MetabolicABSTRACT
Fetal alcohol syndrome (FAS) refers to a pattern of birth defects occurring in a subpopulation of children born to women who consume alcohol during pregnancy. The significant medical, social, and economic impact of FAS is increasing. Particularly hard-hit are African-American and native-American women and children. Over the past two decades, basic and clinical research produced voluminous data on ethanol effects on developing organisms. In 1991, Duester and Pullarkat proposed that competition of ethanol with retinol at the alcohol dehydrogenase (ADH) binding site formed the basis of the FAS mechanism. This competition adversely affects the developing fetus caused by deregulation of retinoic acid (RA) homeostasis essential for proper fetal tissue development. Stated concisely, the FAS hypothesis is: 1. Class I ADH catalyzes the rate-limiting step in oxidation of retinol (ROH) to RA, and ethanol (ETOH) to acetic acid, thus establishing competition for ADH between ROH and ETOH. 2. RA is required as a signal molecule for cell differentiation critical for normal fetal morphogenesis. 3. ADH binds ingested ETOH, thus deregulating RA homeostasis leading to improper RA signal transduction. Preliminary results from molecular modeling studies of ROH-ADH and ETOH-ADH structures, and physiologic pharmacokinetic modeling confirm the hypothesis with remarkable fidelity.
Subject(s)
Alcohol Dehydrogenase/physiology , Computer Simulation , Fetal Alcohol Spectrum Disorders/physiopathology , Models, Molecular , Tretinoin/metabolism , Binding, Competitive/physiology , Ethanol/pharmacokinetics , Female , Homeostasis/physiology , Humans , Infant, Newborn , Pregnancy , Signal Transduction/physiologyABSTRACT
Recovery of acetaldehyde (0-20 microM) or ethanol (0-50 mM) added to blood and subsequently treated with perchloric acid (PCA) was evaluated using head-space gas chromatography and compared with controls. Using blood from five dogs, < 100% of acetaldehyde and ethanol was recovered from PCA-treated samples. Mathematical models of putative binding mechanisms indicated acetaldehyde partitioned simply between supernatant and PCA-induced precipitate and occupied < 1% of acetaldehyde binding sites on precipitate; ethanol partitioned simply between supernatant and precipitate and occupied > 62% of ethanol binding sites. The mathematical model also indicated acetaldehyde binding is 2500-fold stronger than ethanol binding. These results indicate as much as 46.4% of acetaldehyde may be bound to PCA-induced precipitate formed in whole blood. This loss of acetaldehyde is 3- to 4-fold greater than acetaldehyde loss caused by evaporation from PCA-treated blood.