A 42-year-old man is brought to the emergency department due to nausea, vomiting, and blurred vision. He was making his own whiskey with a home moonshine still and started feeling sick after sampling the first several ounces of distillate. Funduscopic evaluation reveals optic disc hyperemia. Laboratory results show a high anion gap metabolic acidosis. It is determined that the patient's symptoms are due to enzymatic conversion of methanol into formate by alcohol dehydrogenase. He is started on fomepizole, a medication that transiently binds to alcohol dehydrogenase and prevents methanol from accessing the enzyme's active site. Which of the following graphs most accurately portrays the change in enzyme kinetics after administration of the antidote?(Black curves = before treatment)

Question

A 42-year-old man is brought to the emergency department due to nausea, vomiting, and blurred vision.  He was making his own whiskey with a home moonshine still and started feeling sick after sampling the first several ounces of distillate.  Funduscopic evaluation reveals optic disc hyperemia.  Laboratory results show a high anion gap metabolic acidosis.  It is determined that the patient's symptoms are due to enzymatic conversion of methanol into formate by alcohol dehydrogenase.  He is started on fomepizole, a medication that transiently binds to alcohol dehydrogenase and prevents methanol from accessing the enzyme's active site.  Which of the following graphs most accurately portrays the change in enzyme kinetics after administration of the antidote?(Black curves = before treatment)

Quizplus · Accepted Answer

11ec160b_3c3b_dcca_9249_410969eb3864_MD0001_00 Methanol itself is relatively nontoxic, primarily causing CNS depression similar to that caused by ethanol. However, once ingested, methanol is converted by alcohol and aldehyde dehydrogenase into formate, a metabolite with pronounced nervous system toxicity (eg, optic nerve destruction, basal ganglia hemorrhage). Treatment of methanol intoxication is targeted at reducing formate production by inhibiting alcohol dehydrogenase. Fomepizole is a competitive inhibitor of alcohol dehydrogenase that decreases the conversion rate of methanol into formate. Ethanol can also be used as a competitive inhibitor, although it is less preferred due to difficulty in dosing. Competitive inhibition occurs when an inhibitor binds to an enzyme (usually at the active site), preventing it from binding the substrate. Because competitive inhibitors compete with the substrate for binding to the active site, higher substrate concentrations are required to reach ½ V_max, thereby increasing apparent K_m. However, competitive inhibitors do not alter enzyme function directly, therefore V_max is unchanged. (Choice B) This graph shows decreased K_m (ie, increased substrate affinity) after treatment, which would increase the toxicity of methanol. (Choices C, D, and E) These graphs show a decrease in V_max (ie, decreased maximum reaction rate) which does not occur with competitive inhibition. Decreased V_max occurs with the use of noncompetitive and mixed inhibitors that bind allosterically to an enzyme; noncompetitive inhibitors do not change the Km, whereas mixed inhibitors can either raise or lower the K_m. Educational objective: Methanol and ethylene glycol have relatively little direct toxicity (similar to ethanol) but are metabolized into highly toxic compounds by alcohol and aldehyde dehydrogenase. Treatment involves administration of fomepizole, a competitive inhibitor of alcohol dehydrogenase (increases K_m without reducing V_max).

A 42-Year-Old Man Is Brought to the Emergency Department Due