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Role of Metabolism in Chemically Induced Nephrotoxicity
Published in Robin S. Goldstein, Mechanisms of Injury in Renal Disease and Toxicity, 2020
Although the kidney is the target organ, cysteine conjugate β-lyase activity is present in liver. The hepatic cytosolic cysteine conjugate β-lyase activity is pyridoxal phosphate (PLP) dependent and is a catalytic property of kynureninase (Stevens, 1985a). As discussed earlier, bacteria in the intestinal microflora also contain cysteine conjugate β-lyase activity (Larsen, 1985). This indicates that other factors, besides the presence of a bioactivating enzyme, are necessary to determine the tissue and cell type specificity of cysteine S-conjugate toxicity, because nontarget tissues also possess the capacity to produce reactive metabolites from cysteine S-conjugates.
Biochemical Effects in Animals
Published in Stephen P. Coburn, The Chemistry and Metabolism of 4′-Deoxypyridoxine, 2018
Amer et al.11 compared the effects of deoxypyridoxine and Schistosoma infection on tryptophan metabolism in mouse liver homogenates. Both deoxypyridoxine and deoxypyridoxine phosphate at 10 pg/ml inhibited kynurenine metabolism. Since formation of kynurenic acid seemed to be reduced more than anthranilic acid, the authors concluded that kynurenine aminotransferase was more susceptible to inhibition than kynureninase. The presence of an equal concentration of pyridoxal partially reversed the inhibition of kynurenic acid synthesis and appeared to stimulate synthesis of anthranilic acid above control values. Pyridoxal phosphate completely reversed the inhibition of kynurenic acid synthesis and again stimulated production of anthranilic acid.
Isoniazid
Published in M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson, Kucers’ The Use of Antibiotics, 2017
Pellagra (niacin deficiency) may occur as a side effect of isoniazid unless supplementary vitamin B6 is given. This may be due to the inhibition of an enzyme (kynureninase) that is involved in the synthesis of NAO from tryptophan. Isoniazid interferes with pyridoxal phosphate, which is a cofactor for kynureninase. Pellagra can occur despite vitamin B6 supplementation (Bender and Russell-Jones 1979; Darvay et al., 1999) in patients with preexisting marginal intake of tryptophan and niacin.
Pharmacokinetics and metabolic disposition of a potent and selective kynurenine monooxygenase inhibitor, CHDI-340246, in laboratory animals
Published in Xenobiotica, 2021
Vinod Khetarpal, Todd Herbst, Diana Shefchek, Steven Ash, Michael Fitzsimmons, Mark Gohdes, Ignacio Munoz-Sanjuan, Celia Dominguez
The metabolism of kynurenine (KYN), formed as a product of tryptophan catabolism, is well known and occurs by three different pathways that are mediated by kynurenine monooxygenase (KMO), Kynureninase (KYNU) and kynurenine amino transferase (KATs) leading to the formation of 3-hydroxykynurenine (3-OH-KYN), anthranilic acid (AA), and kynurenic acid (KYNA), respectively. 3-OH-KYN and AA undergo further metabolism to form 3-hydroxy anthranilic acid (3-OH-AA) by reactions mediated by anthranilate 3-monooxygenase and KYNU, respectively. 3-OH-AA is a substrate of 3-hydroxy anthranilic acid oxidase which converts it to quinolinic acid (QA) through a semialdehyde intermediate. Several studies have implicated dysregulation of the KYN pathway (KP) metabolites in the pathophysiology of Huntington’s disease (HD) and other neurodegenerative diseases (Guidetti et al. 2000; Forrest et al. 2010; Sathyasaikumar et al. 2010), providing evidence that, among various KYN metabolites, 3-OH-KYN and QA are neurotoxic while KYN and KYNA are neuroprotective. KMO is a critical enzyme in the metabolism of KYN and its activity can determine the relative amounts of neuroprotective and neurotoxic metabolites. Therefore, KMO inhibition may have potential as a therapeutic approach for HD by shunting the pathway away from toxic metabolites (3-OH-KYN and QA) and towards the formation of protective metabolites (KYN and KYNA).
Vitamin B-6 and depressive symptomatology, over time, in older Latino adults
Published in Nutritional Neuroscience, 2019
Sandra P. Arévalo, Tammy M. Scott, Luis M. Falcón, Katherine L. Tucker
Vitamin B-6 is a water-soluble compound that comprises three different pyridine derivatives, pyridoxine, pyridoxal, and pyridoxamine, of which PLP is the biologically most active form.19 The coenzyme PLP is an essential cofactor for amino acid decarboxylases involved in the synthesis of neurotransmitters implicated in depression, including dopamine, norepinephrine, serotonin or 5-hydroxytryptamine (5-HT), and γ-amino butyric acid (GABA).20,21 Immune dysregulation and activation of the inflammatory response system are also characteristic of major depression.22 The role of vitamin B-6 in the metabolism of tryptophan and one-carbon metabolism makes vitamin B-6 a relevant cofactor in the body’s immune response.20 Vitamin B-6 prevents the accumulation of neurotoxic intermediates produced during tryptophan metabolism, acting as a cofactor in the metabolism of tryptophan through the kynurenine aminotransferase and kynureninase enzymes.23 Several epidemiological and treatment studies have established an association between low vitamin B-6 status and depressive symptomatology. However, research gaps in the current vitamin B-6 and depression association include the cross-sectional design of the majority of current investigations, the failure to control for relevant confounders, and the dearth of studies examining this association in ethnically diverse populations at high risk for depressive symptomatology.24
Indoleamine 2,3-dioxygenase as a novel therapeutic target for Huntington’s disease
Published in Expert Opinion on Therapeutic Targets, 2019
Fanni A. Boros, Péter Klivényi, József Toldi, László Vécsei
The product of the first enzymatic conversion of the KP, N-formyl-L-kynurenine is converted by formamidase into L-kynurenine (L-KYN). L-KYN represents an important branch point of the pathway as it can be metabolized alternatively into kynurenic acid (KYNA), or anthranilic acid (AA), or 3-hydroxykynurenine (3-HK). KYNA is synthesized from L-KYN by kynurenine aminotransferases (KATs). There are four subtypes of KATs (KATI-IV) [40] that can catalyze the conversion. The principal enzyme from these in the human CNS is KATII [40,41]. Besides KATs, L-KYN can also be metabolized by the kynureninase enzyme (KYNU) and kynurenine 3-monooxygenase (KMO) forming AA or 3-HK, respectively. 3-HK can be metabolized into xanthurenic acid (XA) by KATs, and both AA and 3-HK can be converted into 3-hydroxyanthranilic acid (3-HAA), a metabolite which is a free radical generator (like other compounds of the pathway, see below) [20]. 3-HAA transforms into the unstable 2-amino-3-carboxymuconate-semialdehyde (ACMS) by 3–hydroxyanthranilate oxidase (3-HAO). ACMS can give rise to either picolinic acid (PIC) by conversion via aminocarboxymuconate-semialdehyde decarboxylase (ACMSD) or to QUIN, a NAD+ and NADP+ precursor metabolite, via a non-enzymatic conversion.