Glycol Poisoning Research Articles

Treating ethylene glycol poisoning with alcohol dehydrogenase inhibition, but without extracorporeal treatments: a systematic review

Context Ethylene glycol is metabolized to toxic metabolites that cause acute kidney injury, metabolic acidemia, and death. The treatment of patients with ethylene glycol poisoning includes competitively inhibiting alcohol dehydrogenase with ethanol or fomepizole to prevent the formation of toxic metabolites, and extracorporeal treatments such as hemodialysis to remove ethylene glycol and its metabolites. In the absence of significant metabolic acidemia or kidney injury, it is hypothesized that extracorporeal treatments may be obviated without adverse outcomes to the patient if alcohol dehydrogenase inhibitors are used. Objectives The objectives of this study are to: (1) identify indicators predicting ADH inhibitor failure in patients with ethylene glycol poisoning treated with either ethanol or fomepizole for whom extracorporeal treatment was not performed (aside from rescue therapy, see below) (prognostic study), and (2) validate if the anion gap, shown in a previous study to be the best surrogate for the glycolate concentration, is associated with acute kidney injury and mortality (anion gap study). Methods We conducted a systematic review to identify all reported patients with ethylene glycol poisoning treated without extracorporeal treatments but with either fomepizole (fomepizole monotherapy) or ethanol (ethanol monotherapy). Analyses were performed using both one case per patient and all cases (if multiple events were reported for a single patient). Data were compiled regarding poisoning, biochemistry, and outcomes. Treatment failure was defined as mortality, worsening of acid-base status, extracorporeal treatments used as rescue, or a worsening of kidney or neurological function after alcohol dehydrogenase inhibition was initiated. Also, we performed an analysis of previously described anion gap thresholds to determine if they were associated with outcomes such as acute kidney injury and mortality. Results Of 115 publications identified, 96 contained case-level data. A total of 180 cases were identified with ethanol monotherapy, and 231 with fomepizole monotherapy. Therapy failure was noted mostly when marked acidemia and/or acute kidney injury were present prior to therapy, although there were cases of failed ethanol monotherapy with minimal acidemia (suggesting that ethanol dosing and/or monitoring may not have been optimal). Ethylene glycol dose and ethylene glycol concentration were predictive of monotherapy failure for ethanol, but not for fomepizole. In the anion gap study (207 cases), death and progression of acute kidney injury were almost nonexistent when the anion gap was less than 24 mmol/L and mostly observed when the anion gap was greater than 28 mmol/L. Conclusion This review suggests that in patients with minimal metabolic acidemia (anion gap <28 mmol/L), fomepizole monotherapy without extracorporeal treatments is safe and effective regardless of the ethylene glycol concentration. Treatment failures were observed with ethanol monotherapy which may relate to transient subtherapeutic ethanol concentrations or very high ethylene glycol concentrations. The results are limited by the retrospective nature of the case reports and series reviewed in this study and require prospective validation.

Changes in ionised calcium in cases of ethylene glycol poisoning

Ethylene glycol is a toxic alcohol that occurs in a variety of chemical preparations. In patients poisoned with ethylene glycol, diagnosis is usually based on clinical suspicion and non-specific tests. Hypocalcaemia is often present and results from production of calcium oxalate crystals from oxalic acid. &#x0D; Assess whether reduction in ionized calcium concentration is a common finding in ethylene glycol poisoning, whether it can be appropriate additional marker for the prognosis of outcome.&#x0D; Retrospective clinical records review of patients with a diagnosis of ethylene glycol poisoning at the Riga East University Hospital from 1 January 2012 to 31 December 2020. Ethylene glycol exposure was confirmed retrospectively, qualitatively in all patients. Results of blood gas samples and serum creatinine were analysed and abnormalities were compared amongst various groups.&#x0D; Ionized calcium concentration in arterial blood was below the normal range in 59% of cases at the time of presentation and more commonly associated with a blood pH &lt; 7.3 in 79% of cases. The number of patients with low ionized calcium concentration increased over time. However, the number of patients with blood pH ≥7.3 fell during the same time period. Linear regression analysis did not show a significant correlation between low ionized calcium and blood pH. However, analysis of results from the time of presentation revealed a moderate negative correlation between low ionized calcium concentration and blood pH and lactate concentration. There was also a moderate correlation between low ionized calcium concentration and serum creatinine.&#x0D; A low ionised calcium concentration was a common finding in cases of ethylene glycol poisoning and was more commonly associated with patients exhibiting metabolic acidosis or developing acute kidney injury. Ionised calcium concentration and pH value may be additional markers for the diagnosis and risk stratification of severity from ethylene glycol poisoning.

Mortality and associated risk factors in patients with severe methanol or ethylene glycol poisoning treated with dialysis: a retrospective cohort study.

ObjectiveTo compare the initial clinical course and data on 90-day mortality in adults with methanol (MET) or ethylene glycol (EG) poisoning treated with dialysis.MethodsData on patient demographics and clinical parameters at intensive care unit (ICU) admission and for the first 24 hours after dialysis initiation were collected, and 90-day outcome data were collected for patients with MET (n = 15) or EG (n = 13) poisoning treated with dialysis in this retrospective cohort study.ResultsIn univariate analysis, patients with EG poisoning were older and they had lower hourly urine output during the first 24 hours after the initiation of dialysis. Six (46%) patients with MET poisoning and three (20%) patients with EG poisoning died within 90 days of ICU admission. A larger anion gap and lower pH, bicarbonate levels, base excess, and Glasgow Coma Scale scores on admission, as well as the need for mechanical ventilation, were associated with 90-day mortality.ConclusionsMetabolic acidosis, a large anion gap, and an altered mental status on admission appear to be associated with mortality in MET or EG poisoning, and EG poisoning may be linked to lower urine output.

Prompt Diagnosis of Ethylene Glycol Intoxication by an Unusual "Lactate Gap": A Case Report.

IntroductionEthylene glycol intoxication can be lethal if diagnosis is delayed. Often, prompt diagnosis may need to be based on indirect laboratory findings.Case reportWe present a case of severe ethylene glycol intoxication whose diagnosis was based on an unusual “lactate gap.” The patient responded well to the treatment and had a full recovery.ConclusionA “lactate gap” can be helpful in establishing a diagnosis of ethylene glycol intoxication.

Fox (Vulpes vulpes) involvement identified in a series of cat carcass mutilations.

This study was designed to identify the cause of mutilation and death in 32 cats, part of a larger cohort found dead in Greater London, the United Kingdom, between 2016 and 2018. At the time, discussion in the media led to concerns of a human serial cat killer (dubbed The Croydon Cat Killer) pursuing domestic cats, causing a state of disquietude. Given the link between animal abuse and domestic violence, human intervention had to be ruled out. Using a combination of DNA testing, computed tomography imaging, and postmortem examination, no evidence was found to support any human involvement. Instead, a significant association between cat carcass mutilation and the presence of fox DNA was demonstrated. Gross examination identified shared characteristics including the pattern of mutilation, level of limb or vertebral disarticulation, wet fur, wound edges with shortened fur, and smooth or irregular contours, and marks in the skin, muscle, and bone consistent with damage from carnivore teeth. Together these findings supported the theory that the cause of mutilation was postmortem scavenging by red foxes (Vulpes vulpes). The probable cause of death was established in 26/32 (81%) carcasses: 10 were predated, 8 died from cardiorespiratory failure, 6 from blunt force trauma, one from ethylene glycol toxicity, and another from liver failure. In 6 carcasses a cause of death was not established due to autolysis and/or extensive mutilation. In summary, this study highlights the value of a multidisciplinary approach to fully investigate cases of suspected human-inflicted mutilation of animals.

Case report: transcaval impella placement in a patient with acute lv dysfunction from ethylene glycol toxicity

Introduction: Ethylene glycol is a toxic alcohol commonly found in antifreeze, or other household and industrial agents. Patients usually survive ethylene glycol toxicity when promptly treated but delay in care can cause significant morbidity and mortality. Significant metabolic acidosis can lead to multisystem organ dysfunction including Left ventricular dysfunction which can pose a unique challenge. Case report: The patient is a young female who presented with acute encephalopathy, intraventricular hemorrhage (IVH), severe metabolic acidosis, and severe left ventricular dysfunction following acute ethylene glycol toxicity. A diagnosis was quickly made due to presence of calcium oxalate crystals in the urine. The patient received timely interventions with Fomepizole and kidney replacement therapy (KRT), which failed to reverse her severe shock. The patient required mechanical circulatory support (MCS) in the form of Transcaval peripheral ventricular assist device (pVAD). Conclusion: This case showed the use of the transcaval approach to place an pVAD in a young patient suffering from ethylene glycol toxicity and severe left ventricular dysfunction. Although it remains an uncommon approach, it can be used when more traditional access points have failed, and the patient requires MCS.

Fomepizole as an adjunct in acetylcysteine treated acetaminophen overdose patients: a case series

Introduction Acetaminophen (N-acetyl-para-aminophenol or APAP) is the leading cause of acute liver failure worldwide. Standard therapy for APAP overdose is with IV N-acetylcysteine (NAC). However, overdose patients treated with NAC can still incur hepatotoxicity in some circumstances. Fomepizole has proven safety in methanol and ethylene glycol poisoning and is a potent CYP2E1 and c-Jun-N-terminal Kinase (JNK) inhibitor that is effective even in the metabolic phase. Methods We present a prospective case series of 14 consecutive, high-risk patients who had elevated APAP levels after overdose who were treated with fomepizole as an adjunct to standard IV-NAC. The attending toxicologist utilized clinical judgement to determine the use of fomepizole, especially if APAP levels persisted due to altered half-life or risk factors for toxicity. Results There were no unfavorable outcomes in any patient, which were better than expected. Conclusions This case series has demonstrated the safety of fomepizole in high-risk APAP overdose. The efficacy of fomepizole needs to be further elucidated through controlled clinical trials on a larger scale. In massive APAP overdoses, fomepizole should be considered as an adjunct due to the known failure rate of NAC and the safety profile of fomepizole.

COMBINATION THERAPY WITH N-ACETYLCYSTEINE AND 4-METHYLPYRAZOLE FOR ACETAMINOPHEN OVERDOSE

TOPIC: Critical Care TYPE: Medical Student/Resident Case Reports INTRODUCTION: Acetaminophen (APAP) overdose is the most common cause of acute liver failure in the United States. We report a case of a patient who presented with acetaminophen overdose and was successfully treated with N-acetylcysteine (NAC) and 4-methylpyrazole (4-MP). CASE PRESENTATION: A 58-year-old female with history of alcohol abuse, hypertension, and hyperlipidemia presented with abdominal pain, nausea, and vomiting. Patient had fallen several days prior, resulting in rib fractures, and had been taking APAP for pain relief. Vital signs were within normal limits. Physical exam showed a lethargic, encephalopathic patient who only followed simple commands and had right upper quadrant abdominal tenderness. Labs revealed total bilirubin 6.4, AST 19816, ALT 5544, INR 3.7, acetaminophen level 58.3, lactic acid 12.2, creatinine 3.1, lipase 1187, and ammonia 82. Imaging was consistent with hepatic steatosis. Patient was treated with aggressive fluid resuscitation for pancreatitis; NAC and 4-MP for acetaminophen toxicity; lactulose and rifaximin for hepatic encephalopathy; vitamin K for coagulopathy; and albumin, octreotide, and midodrine for hepatorenal syndrome. Mental status and lab abnormalities gradually improved and acetaminophen level became undetectable. DISCUSSION: Our patient presented with unintentional APAP overdose. She likely had underlying chronic liver disease, as evidenced by hepatic steatosis on imaging, due to alcohol abuse. This likely made her more susceptible to liver injury, even with therapeutic doses of APAP.The pathogenesis APAP-induced hepatotoxicity starts with the conversion of APAP to N-acetyl-p-benzoquinone imine (NAPQI) by cytochrome P450 enzymes, which is detoxified by conjunction with glutathione.[1] When excessive amounts of APAP are ingested, hepatic glutathione levels are depleted, resulting in oxidant stress. NAC, the current standard of care and only clinically approved treatment for APAP overdose, attempts to limit this by accelerating glutathione synthesis and subsequent scavenging of NAPQI.[2]Recent literature has suggested that 4-MP may also be beneficial for attenuating liver injury in APAP overdose. 4-MP is classically known for its inhibition of alcohol dehydrogenase in methanol or ethylene glycol poisoning. However, it is unique in that it also directly inhibits CYP2E1, one of the major enzymes involved in the generation of NAPQI. 4-MP has been shown to be effective at preventing APAP-induced liver injury in mice and human hepatocytes and limiting oxidative metabolism in five human volunteers who ingested supratherapeutic APAP doses.[1,2] It may also protect against APAP-induced nephrotoxicity via a similar mechanism.[3] CONCLUSIONS: In patients presenting with APAP overdose, combination therapy with NAC and 4-MP may provide complementary protective effects through targeting of different therapeutic pathways. REFERENCE #1: Kang AM, Padilla-Jones A, Fisher ES, et al. The effect of 4-methylpyrazole on oxidative metabolism of acetaminophen in human volunteers. J Med Toxicol. 2020;16(2):169-176. REFERENCE #2: Akakpo JY, Ramachandran A, Kandel SE, et al. 4-Methylpyrazole protects against acetaminophen hepatotoxicity in mice and in primary human hepatocytes. Hum Exp Toxicol. 2018;37(12):1310-1322. REFERENCE #3: Akakpo JY, Ramachandran A, Orhan H, et al. 4-methylpyrazole protects against acetaminophen-induced acute kidney injury. Toxicol Appl Pharmacol. 2020;409:115317. DISCLOSURES: No relevant relationships by Travis Homan, source=Web Response No relevant relationships by Brittany Wichman, source=Web Response

Fomepizole dosing during continuous renal replacement therapy – an observational study

Background Fomepizole is the preferred antidote for treatment of methanol and ethylene glycol poisoning, acting by inhibiting the formation of the toxic metabolites. Although very effective, the price is high and the availability is limited. Its availability is further challenged in situations with mass poisonings. Therefore, a 50% reduced maintenance dose for fomepizole during continuous renal replacement therapy (CRRT) was suggested in 2016, based on pharmacokinetic data only. Our aim was to study whether this new dosing for fomepizole during CRRT gave plasma concentrations above the required 10 µmol/L. Secondly, we wanted to study the elimination kinetics of fomepizole during CRRT, which has never been studied before. Methods Prospective observational study of adult patients treated with fomepizole and CRRT. We collected samples from arterial line (pre-filter) = plasma concentration, post-filter and dialysate for fomepizole measurements. Fomepizole was measured using high-pressure liquid chromatography with a reverse phase column. Results Ten patients were included in the study. Seven were treated with continuous veno-venous hemodialysis (CVVHD) and three with continuous veno-venous hemodiafiltration (CVVHDF). Ninety-eight percent of the plasma samples were above the minimum plasma concentration of 10 µmol/L. Fomepizole was removed during CRRT with a median saturation/sieving coefficient of 0.85 and dialysis clearance of 28 mL/min. Conclusion Fomepizole was eliminated during CCRT. The new dosing recommendations for fomepizole and CRRT appeared safe, by maintaining the plasma concentration above the minimum value of 10 µmol/L. Based on these data, the fomepizole maintenance dose during CRRT could be reduced to half as compared to intermittent hemodialysis.

Ethylene Glycol Intoxication Requiring ECMO Support

Ethylene glycol is commonly used in antifreeze, and ingestion of even a small amount can result in acute kidney injury, severe metabolic acidosis, and neurological injury. When cases are recognized early, treatment involves administration of alcohol dehydrogenase inhibitors to prevent conversion to toxic metabolites of glycolate, glyoxolate, and oxalate. In later presentations with more severe renal injury, hemodialysis may be required for clearance of toxic metabolites and supportive care for renal failure. We present the first reported case of severe ethylene glycol intoxication requiring support of extracorporeal membrane oxygenation (ECMO) due to refractory cardiopulmonary collapse.

Ethylene glycol poisoning treated using combination of ethanol and haemodialysis therapy instead of fomepizole: a case report

We report a case of ethylene glycol poisoning in a 70-year-old man with headache and dysarthria. Blood tests showed a marked increase in the anion gap (29.8 mOsm/kg) and osmotic gap (14 mOsm/kg). The estimated blood concentration of ethylene glycol was 86.8 mg/dL. Ethanol was administered and he underwent haemodialysis for 7 cycles, which was discontinued on day 12. Fomepizole, which competes with alcohol dehydrogenase, is an effective treatment for ethylene glycol poisoning. However, it is usually prescribed within 24 h after poisoning, and studies on its use in cases of severe acute renal injury over time are limited. We were able to obtain good results with haemodialysis without using fomepizole. Conventional treatments such as haemodialysis may be more useful than fomepizole in terms of cost benefits in patients with addiction who have been taking the drug for a long time or who have advanced renal injury.  Â

Une intoxication de diagnostic histologique

Ethylene glycol poisoning is relatively rare, with around a hundred cases reported each year in France. Its diagnosis is often challenging and delayed because of a several hours' free interval between ingestion of the toxic and the onset of the first symptoms. Ethylene glycol is a colorless and odorless liquid primarily found in automotive coolants, whose toxicity is linked to its hepatic metabolites. Histologically, ethylene glycol poisoning is characterized by abundant tissular deposits of calcium oxalate crystals. Under polarized light, these crystals appear birefringent and iridescent. Their microscopic appearance and their distribution are pathognomonic of oxalosis. Due to its frequent misleading presentation, the diagnosis of ethylene glycol poisoning is sometimes only made after an autopsy. Hereafter, we report the case of a 59-year-old man diagnosed with ethylene glycol intoxication after a post-mortem histopathological examination of organs.

The effective ethanol rate against the toxicity of ethylene glycol

Ethylene glycol (EG) is a toxic substance and EG metabolites cause metabolic acidosis. The major emphasis in this study is to get rid of the toxicity of EG before conversion to its metabolites. The interaction between ethylene glycol and ethanol has been studied using DFT (Density functional theory method). In ethylene glycol metabolites in the blood; Glycolic acid is more stable and gloxal less stable. The interaction of ethylene glycol with ethanol has been considered for ethylene glycol metabolism. Thermodynamic values obtained from ethylene glycol metabolites and ethanol were also analyzed. According to the analyst results of ethanol and ethylene glycol ratios; The maximum effective point is very stable in the blood and its solubility is determined at this rate. It is very important to determine the most appropriate rate in the prevention of toxicity. This study is an important study in terms of the use of ethanol in the prevention of toxicity of EG, the first of its rates and in terms of preventing the loss of time and substance.

Impact of propylene- and ethylene glycol-based deicing materials on the environment and airports infrastructure

Snow, frost and ice formations on aircraft surfaces have a negative impact on aerodynamic and operational properties of aircraft. Ethyleneglycol and propyleneglycol are the most used components of liquids for aircraft deicing that have an environmental impact. Deicing agents are toxic and pollute the environment when they enter soil or water bodies. These substances evaporate during the treatment of aircraft and in the case of ethylene glycol have an unpleasant dizzying odor that enters the air and is carried by air currents. Deicing materials can cause problems with corrosion of maintenance materials (aircraft skin, engine blades, aerodrome coating, etc.). The article analyzes a large amount of domestic and foreign technical and regulatory information, which allowed a comprehensive comparison of physicochemical and operational properties of propylene- and ethylene glycol-containing deicing materials, as well as to investigate their impact on ecosystem components, including the humans. Comparative studies show that propylene glycol is inert to living organisms and humans. Ethylene glycol adversely affects reproductive function, metabolism, immune system and reduces haemoglobin. The LD50 (total toxicity indicator) of ethylene glycol is more than 4 times lower compared to propylene glycol, which confirms the extremely high toxicity of ethylene glycol and deicing substances containing it. Propylene glycol-based deicing fluids are more environmentally friendly due to low toxicity, increased biodegradation under the same operational requirements

Response to "Ethylene glycol poisoning: A diagnostic challenge in a patient with persistent seizures and a severe metabolic acidosis".

Response to "Ethylene glycol poisoning: A diagnostic challenge in a patient with persistent seizures and a severe metabolic acidosis".

Effet du stiripentol sur l’excrétion urinaire d’oxalate

Oxalate is a metabolite promoting the formation of calcium oxalate crystals in urine. Hyperoxaluria is a feature of genetic diseases, known as primary hyperoxaluria, leading to chronic kidney disease. Ethylene glycol poisoning induces the crystallization of calcium oxalate crystals in renal tubules, promoting acute renal failure. Urine oxalate results from glyoxylate transformation to oxalate in the liver, due to lactate dehydrogenase (LDH) activity, especially the LDH-5 isoenzyme. Genetic RNA interference therapy targeting lactate dehydrogenase lowers urine oxalate excretion in murine models. Stiripentol is a drug inhibiting neuronal LDH-5 isoenzyme activity. We hypothesized that stiripentol would also reduce hepatic oxalate production and urine oxalate excretion. In vitro Stiripentol decreases oxalate synthesis by hepatocytes. In vivo, stiripentol decreases urine oxalate excretion in rats and protects kidney tissue and function against ethylene glycol intoxication and hydroxyproline-induced calcium oxalate crystalline nephropathy. The use of stiripentol in clinical practice deserves further clinical studies.

Chronic exposure of industrial grade calcium carbide and ethylene glycol alter histological architecture of systemic organs by disrupting redox balance in rat.

The threat to human health or the surroundings by the use of artificial fruit ripening agents has become a global concern. Calcium carbide (CaC2) and ethylene glycol (EG) are the two widely using ripening agents. The present study evaluates the toxic effect of chronic exposures of CaC2 and EG in rats. CaC2 and EG were administered to the rats for 180days orally. The alterations in oxido-reduction status, haematological, biochemical and histopathological parameters were analysed. Arsenic content in CaC2 and animal samples were detected by atomic absorption spectrometer and phosphorus by molybdate-UV method. At chronic doses, there were no significant alterations in haematological and biochemical parameters except in creatinine level especially by EG. However, histological details revealed microvesicular fatty change in liver, corpuscles degeneration in kidney and lymphocytes infiltration in various tissues. In intestine, the mucosal lesion scoring was found high (p<0.01). SOD and CAT activities and GSH level was reduced significantly by CaC2 administration (p<0.01). Arsenic and phosphorus detected is above the toxic level: 7.222 and 13.91mg/dL in CaC2, 1.634 and 6.22mg/dL in blood and 0.563 and 6.99mg/dL in liver, respectively. The study suggests that the industrial grade CaC2 and EG induce systemic toxicity to rats and the liver is the most susceptible organ. The CaC2 and EG toxicity is mediated through the upset of redox balance and subsequent inflammatory responses. This could be due to the presence of arsenic and phosphorus contents that detected above the normal level in the industrial grade CaC2.

Outcomes of death and prolonged renal insufficiency in ethylene glycol poisoned patients.

Despite the severity of ethylene glycol intoxication, there is a paucity of studies that analyze prognostic factors. This study aims to determine prognostic factors with impact on core outcomes like death and prolonged kidney injury (KI) in ethylene glycol poisoned patients. We retrospectively assessed prevalence, clinical and biochemical features in one large data set from two regional hospitals from the North-East region of Romania, between January 2012 and October 2017. Secondly, we compared prognostic factors of cases treated with dialysis plus antidote (N = 28 patients) with cases who received antidote only and supportive therapy (N = 28 patients). Of the 56 cases included, 16 deaths (28.57%) were recorded. The symptomatology at admission was more severe among patients requiring hemodialysis: a lower mean value for initial pH, lower initial alkaline reserve (AR) and higher mean values for initial serum creatinine (Cr1). The data analysis (survivors/deceased) showed a correlation between pH, Glasgow Coma Score (GCS), and increased mortality. In addition, we found a correlation between initial mean values for pH, AR (mmol/L), Cr1 (mg/dL), and peak Cr24 (mg/dL) with outcomes of RI or death. Compared with survivors, patients who died or had prolonged kidney injury were more likely to exhibit clinical signs such as coma, seizures, and acidosis. Hemodialysis and antidote should be started early and continued until acidosis is corrected.

MANAGEMENT OF THE EMERGENCY DEPARTMENT PATIENT WITH TOXIC ALCOHOL POISONING

The aim of the study is to present the process of diagnosis and treatment of the patients poisoned with toxic alcohols. Furthermore, the suicide risk assessment was presented. The role of supportive cure and the importance of the treatment with alcohol dehydrogenase blockade with fomepizole or ethanol hemodialysis for severe intoxicated patients were presented. The differences in the treatment of poisoning with particular toxic alcohols were presented. Moreover, the important psychological factors in the management of this group of patients were also discussed. The paper was illustrated with typical case studies of patients suffering from methanol and ethylene glycol intoxication. Conclusions: 1. The recognition of toxic alcohol poisoning remains a challenge for the clinician, because nonspecific symptoms are similar in many other conditions. 2. Proper management of the poisoned patients requires thorough analysis of many aspects: circumstances of the event, laboratory findings, response to the treatment, and the patient’s psychological problems.

The Role of Alcohol Dehydrogenase in Drug Metabolism: Beyond Ethanol Oxidation.

Alcohol dehydrogenases (ADHs) are most known for their roles in oxidation and elimination of ethanol. Although less known, ADHs also play a critical role in the metabolism of a number of drugs and metabolites that contain alcohol functional groups, such as abacavir (HIV/AIDS), hydroxyzine (antihistamine), and ethambutol (antituberculosis). ADHs consist of 7 gene family numbers and several genetic polymorphic forms. ADHs are cytosolic enzymes that are most abundantly found in the liver, although also present in other tissues including gastrointestinal tract and adipose. Marked species differences exist for ADHs including genes, proteins, enzymatic activity, and tissue distribution. The active site of ADHs is relatively small and cylindrical in shape. This results in somewhat narrow substrate specificity. Secondary alcohols are generally poor substrates for ADHs. In vitro-in vivo correlations for ADHs have not been established, partly due to insufficient clinical data. Fomepizole (4-methylpyrazole) is a nonspecific ADH inhibitor currently being used as an antidote for the treatment of methanol and ethylene glycol poisoning. Fomepizole also has the potential to treat intoxication of other substances of abuse by inhibiting ADHs to prevent formation of toxic metabolites. ADHs are inducible through farnesoid X receptor (FXR) and other transcription factors. Drug-drug interactions have been observed in the clinic for ADHs between ethanol and therapeutic drugs, and between fomepizole and ADH substrates. Future research in this area will provide additional insights about this class of complex, yet fascinating enzymes.