Suicide metabolite

Another exception to the tendency for initial biotransformation products to be readily directed into subsequent steps in common metabolic pathways involves the formation of so-called suicide metabolites (Knackmuss, 1981). These problematic products result when the biological transformations yield a compound which subsequently attacks the enzymes involved. If this attack debilitates one of these enzymes, the successful operation of the relevant metabolic pathway is stopped. An example is the production of acyl halides from 3-halocatechol in certain microorganisms (e.g., Bartels et al., 1984) ... 

In a subsequent step, the enzyme adduct then detaches the alkyl group as an alcohol product. Sometimes, monohalogenated compounds act as growth inhibitors because the adduct formed is difficult to hydrolyze and thereby incapacitates the enzyme (recall suicide metabolites). However, assuming the adduct can be hydrolyzed, then the enzyme is prepared to serve again. 

So far, evidence for abnormal peripheral (Elliott 1992) or central (Horton 1992) monoamine function in depression is equivocal, and no consistent biochemical markers have emerged to provide a firm link between the two (Table 20.2). One widely cited finding is that subjects who have attempted violent suicide form a neurochemically distinct group because the concentration of the 5-HT metabolite, 5-HIAA, in their CSF is lower than normal, suggesting that a deficit in 5-HT release is associated with suicide... 

Disulfiram works by irreversibly blocking the enzyme aldehyde dehydrogenase, a step in the metabolism of alcohol, resulting in increased blood levels of the toxic metabolite acetaldehyde. As levels of acetaldehyde increase, the patient experiences decreased blood pressure, increased heart rate, chest pain, palpitations, dizziness, flushing, sweating, weakness, nausea and vomiting, headache, shortness of breath, blurred vision, and syncope. These effects are commonly referred to as the disulfiram-ethanol reaction. Their severity increases with the amount of alcohol that is consumed, and they may warrant emergency treatment. Disulfiram is contraindicated in patients who have cardiovascular or cerebrovascular disease, because the hypotensive effects of the disulfiram-alcohol reaction could be fatal in such patients or in combination with antihypertensive medications. Disulfiram is relatively contraindicated in patients with diabetes, hypothyroidism, epilepsy, liver disease, and kidney disease as well as impulsively suicidal patients. 

Mann, J. J., Malone, K. M., Sweeney, J. A. et al. Attempted suicide characteristics and cerebrospinal fluid amine metabolites in depressed inpatients. Neuropsychopharm. 15 576-586,1996. 

Thus, it would be reasonable to expect that the acetylenic group would be metabolized to a carboxylic acid. While the acid metabolite has not been detected, ethinyl estradiol is a suicide substrate inhibitor of CYP2B6 consistent with a reactive ketene being formed as an intermediate (142). In addition, there is a rearrangement product (4) shown in Figure 4.75. 

Irreversible CYP inhibition can arise from different chemical mechanisms. However, a common initial step is the metabolic activation of a substrate into a reactive metabolite that is trapped within the active site of the CYP to form a tightly bound complex causing a long-lasting inactivation of enzyme activity. Enzymatic activity can be restored only through the new synthesis of the enzyme. For this reason, irreversible CYP inhibition is often referred to as mechanism-based inhibition , metabolite-based inhibition or suicide inhibition . 

When reactive metabolites are formed by metabolic activation, some of them can escape from the active site and bind to external protein residues or be trapped by reduced glutathione (GSH) or other nucleophiles. The remaining molecules that are not released from the active site will cause the suicide inhibition [7]. The ratio of the number of reactive molecules remaining in the active site and those escaping is a measure of the reactivity of the intermediates formed. The addition of scavengers or GSH to the incubation mixture does not affect and cannot prevent the CYP mechanism-based inhibition. However, GSH can reduce the extent of the nonspecific covalent binding to proteins by those reactive molecules that escape from the active site. In contrast, addition of substrates or inhibitors that compete for the same catalytic center usually results in reduction of the extent of inhibition. 

Oral exposure to cyanide usually results from accidental, homicidal, or suicidal ingestion of cyanide salts. Sodium cyanide and potassium cyanide are the most frequently studied cyanide compounds. Copper cyanide, potassium silver cyanide, silver cyanide, and calcium cyanide are other compounds that humans could encounter through oral or dermal exposure. Cassava roots and certain fruit pits contain compounds that can be broken down to form cyanide. Cassava roots form the staple diet of some populations in Africa, Central and South America, and Asia. However, it must be noted that cassava roots are notoriously deficient in protein and other nutrients and contain many other compounds, in addition to cyanide, that could be responsible for some of the observed toxic effects. Thiocyanate is a metabolite of cyanide that is formed in the body after exposure to cyanide compounds. When possible, all oral exposures are expressed as mg CN/kg/day. 

The role of serotonin (5-hydroxytryptamine, 5-HT) has also been extensively studied in depressed patients. Whereas the overall psycho-physiological effects of noradrenaline in the CNS appear to be linked to drive and motivation, 5-HT is primarily involved in the expression of mood. It is not surprising therefore to find that the serotonergic system is abnormal in depression. This is indicated by a reduction in the main 5-HT metabolite, 5-hydroxy indole acetic acid (5-HIAA), in the cerebrospinal fluid of severely depressed patients and a reduction in 5-HT and 5-HIAA in the limbic regions of the brain of suicide victims. The 5-HT receptor function also appears to be abnormal in depression. This is indicated by an increase in the density of cortical 5-HT2a receptors in the brains of suicide victims and also on the platelet membrane of depressed patients. Platelets may be considered as accessible models of the nerve terminal. 

Fentanyl, a potent synthetic narcotic analgesic, and norfentanyl were determined in postmortem samples nsing liqnid-liquid extraction (LLE) and HPLC-ESI(h-)-MS-MS enabling the authors to determine the distribntion of parent compound and metabolite in tissnes and organs of a suicidal fatality case [36]. However, matrix effects were not investigated. 

Low cerebrospinal fluid (CSF) concentrations of homovanillic acid, a dopamine metabolite, were associated with suicide attempts in two pediatric studies (Kruesi et al., 1992 L. Greenhill, personal communication). 

In essentially all species of animals, including humans, serotonin is important in aggression (Kravitz, 2000). Relationships between CSF concentrations of a serotonin metabolite, 5-hydroxyindoleacetic acid (5-HIAA), and human aggression were described in As-berg et al. s landmark study (1976), which showed a bimodal distribution among depressed patients. A meta-analysis of 27 studies, involving 1202 psychiatric patients, showed an association between attempted suicide and low levels of CSF 5-HIAA (Lester, 1995). 

Lester, D. (1995) The concentration of neutottansmitter metabolites in the cerebrospinal fluid of suicidal individuals a meta-analysis. Pharmacopsychiatry 28(2) 45-50. 

Bowden CL, Huang LG, Javors MA, et al Calcium function in affective disorders and healthy controls. Biol Psychiatry 23 367-376, 1988 Bowden C, Cheetham SC, Crompton MR, et al Dopamine and its metabolites in depressed suicide victims (abstract). Can J Physiol Pharmacol 72 (suppl 1) 386,... 

An association between impulsive aggression, suicidal behavior, or both with decreased CSF levels of the serotonin metabolite 5-HIAA... 

Studies of depressed patients have sometimes shown an alteration in monoamine function. For example, some studies have found evidence of alteration in serotonin receptor numbers (5-HT1A and 5-HT2c) or norepinephrine (k2) receptors in depressed and suicidal patients, but these findings have not been consistent. A reduction in the primary serotonin metabolite 5-hydroxyindoleacetic acid in the cerebrospinal fluid is associated with violent and impulsive behavior, including violent suicide attempts. However, this finding is not specific to major depression and is associated more generally with violent and impulsive behavior. 

Acetaminophen is one of the drugs commonly involved in suicide attempts and accidental poisonings, both as the sole agent and in combination with other drugs. Acute ingestion of more than 150-200 mg/kg (children) or 7 g total (adults) is considered potentially toxic. A highly toxic metabolite is produced in the liver (see Figure 4-5). 

Reactive metabolites of xenobiotics may differ in reactivity, and therefore have varying impact on enzymatic activities in terms of proximity to their origin. For example, some intermediates are highly reactive and directly inhibit the enzyme that leads to their formation. These substances are commonly referred to as suicide inhibitors, for obvious reasons. Some suicide inhibitors, such as piperonyl butoxide (PBO), a pesticide synergist) are common inhibitors of certain CYP isozymes. PBO amplifies the toxicity of certain insecticides by inhibiting the insect s CYP enzymes that are involved in its degradation. It is metabolized to a highly reactive carbene, which forms an inhibitor complex with the heme iron of CYP, as shown in Scheme 3.6. 

Metabolites that are less reactive than suicide inhibitors may impact more distant enzymes, within the same cell, adjacent cells, or even in other tissues and organs, far removed from the original site of primary metabolism. For example, organopho-sphates (OPs), an ingredient in many pesticides, are metabolized by hepatic CYPs to intermediates, which, when transported to the nervous system, inhibit esterases that are critical for neural function. Acetylcholinesterase (AChE) catalyzes the hydrolysis of the ester bond in the neurotransmitter, acetylcholine, allowing choline to be recycled by the presynaptic neurons. If AChE is not effectively hydrolyzed by AChE in this manner, it builds up in the synapse and causes hyperexcitation of the postsynaptic receptors. The metabolites of certain insecticides, such as the phos-phorothionates (e.g., parathion and malathion) inhibit AChE-mediated hydrolysis. Phosphorothionates contain a sulfur atom that is double-bonded to the central phosphorus. However, in a CYP-catalyzed desulfuration reaction, the S atom is... 

Few strong biological findings demonstrating lesions in specific psychiatric disorders Example discovery of changes in serotonin receptors and metabolites in depression, schizophrenia, and suicidal behavior... 

These are metabolites that bind primarily to the parent enzyme. This category includes substrates that form enzyme-bound intermediates that react with the active site of the enzyme. Such chemicals are known as suicide substrates. A number of compounds are known to react in this manner with CYP, and such compounds are often used experimentally as CYP inhibitors (see the discussion of piperonyl butoxide, Section 7.2.2). Other compounds, although not true suicide substrates, produce reactive metabolites that bind primarily to the activating enzyme or adjacent proteins altering the function of the protein. 

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