Metabolism dependant toxicity

Nelson SD, Trager WF. The use of deuterium isotope effects to probe the active site properties, mechanism of cytochrome P450-catalyzed reactions, and mechanisms of metabolically dependent toxicity. Drug Metab Dispos 2003 31(12) 1481—1498. 

Gurtoo HL, Hipkens HJ, Sharma SD. 1981. Role of glutathione in the metabolism-dependent toxicity and chemotherapy of cyclophosphamide. Cancer Res 41 (9 Part 1 ) 3584-3591. 

Gurtoo HL, Berrigan MJ, Love J, et al. 1985. Metabolism-dependent toxicities of cyclophosphamide and protection by N-acetylcysteine and other thiols. Cancer Treat Res 24 61-79. 

Pirmohamed M, Coleman MD, Hussain F, Breckenridge AM, Park BK. Direct and metabolism-dependent toxicity of sulphasalazine and its principal metabolites towards human erythrocytes and leucocytes. Br J Clin Pharmacol 1991 32(3) 303-10. 

The literature emphasizes that arsenic metabolism and toxicity vary greatly between species and that its effects are significantly altered by numerous physical, chemical, and biological modifiers. Adverse health effects, for example, may involve respiratory, gastrointestinal, cardiovascular, and hematopoietic systems, and may range from reversible effects to cancer and death, depending partly on the physical and chemical forms of arsenic tested, the route of administration, and the dose. 

The herbicide alachlor (4.146, Fig. 4.7) also displayed species-dependent toxicity, since it induced nasal tumors in rats but not in mice. Its metabolic scheme in rats and mice (Fig. 4.7) shows that alachlor can be transformed into 2,6-diethylaniline (4.149) by two different pathways, one of which proceeds via formation of 4.147. The other pathway implies glutathione (GSH) conjugation, followed by /3-lyase-mediated liberation of the thiol, followed by S-methylation to produce the methylsulfide 4.148. The two secondary amides 4.147 and 4.148 were hydrolyzed by microsomal arylamidases, but alachlor itself was not a substrate for this enzyme. The hydrolytic product 2,6-diethylaniline (4.149) was oxidized in nasal tissues to the electrophilic quinonimine metabolite 4.150, which can bind covalently to proteins. Aryl-... 

Wang P-Y, Kaneko T, Sato A, et al. 1995. Dose and route dependent alteration of metabolism and toxicity of chloroform in fed and fasting rats. Toxicol Appl Pharm 135(1) 119-126. 

Chlorpromazine Blockade of D2 receptors >> 5 2 receptors .-Receptor blockade (fluphenazine least) muscarinic (M)-receptor blockade (especially chlorpromazine and thioridazine) Hx-receptor blockade (chlorpromazine, thiothixene) t central nervous system (CNS) depression (sedation) t decreased seizure threshold t QT prolongation (thioridazine) Psychiatric schizophrenia (alleviate positive symptoms), bipolar disorder (manic phase) nonpsychiatric antiemesis, preoperative sedation (promethazine) pruritus Oral and parenteral forms, long half-lives with metabolism-dependent elimination Toxicity Extensions of effects on a - and M- receptors blockade of dopamine receptors may result in akathisia, dystonia, parkinsonian symptoms, tardivedyskinesia, and hyperprolactinemia... 

Haloperidol Blockade of D2 receptors >> 5HT2A receptors Some a blockade, but minimal M receptor blockade and much less sedation than the phenothiazines Schizophrenia (alleviates positive symptoms), bipolar disorder (manic phase), Huntington s chorea, Tourette s syndrome Oral and parenteral forms with metabolism-dependent elimination Toxicity Extrapyramidal dysfunction is major adverse effect... 

Enzyme inhibition. The enzymes of biotransformation may be inhibited by a single exposure to chemicals. This occurs by several mechanisms formation of a complex, competition between substrates, destruction of the enzyme, reduced synthesis of the enzyme, allosteric effects, and lack of cofactors. The consequences will depend on the role of metabolism in toxicity in the same way as induction (see above). 

Induction of the MPT requires Ca2+ conversely, plasma membrane and ER Ca2+ pumps require ATP. One of the earliest effects of CCb is metabolism-dependent inhibition of the ER Ca2+ pump through oxidation of a critical -SH residue. A similar oxidant-sensitive -SH residue is present in the plasma membrane Ca2+ pump. Thus, the reciprocal requirements of Ca2+ for the MPT and ATP for cellular Ca2+ pumps provide a mechanism for linkage of ATP depletion and disruption of Ca2+ homeostasis as mediators of cell death. Most proximal toxic effects that lead to hepatocellular mitochondrial and Ca2+ dysfunction can be generalized into two classes, those involving production of oxidative stress or formation of reactive metabolites. 

The antipsychotic chlorpromazine is a prototype heptotoxicant for production of cholestasis. Pleiotropic effects of chlorpromazine on membrane permeability and associated ion gradients and microfilament-mediated canalicular contraction have been attributed to detergent effects. Valproic acid, an anticonvulsant, is associated with microvesicular steatosis. Inhibition of mitochondial fatty acid (S-oxidation is an important component of this toxic effect and is apparently related to carnitine availability as evidenced by the protection afforded by L-carnitine supplements. The hypolipidemic drugs clofibrate, fenofibrate, and gemfibrozil are peroxisome prolif-erators in rodent liver, but not in humans. Isoniazid, an antibiotic used to treat tuberculosis, exhibits an approximately 1 % incidence of hepatotoxicity. Although toxicity is known to be metabolism-dependent and protein adduction has been well-... 

In an effort to elucidate the nature of endocyclic iminium-derived species that give rise to metabolism-dependent covalent binding and to clarify what factors govern the balance between toxic activation and detoxication... 

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