Role of Biotransformation in Conceptal Toxicity of Drugs and Other Chemicals

Kulkarni, Arun P.

doi:10.2174/1381612013397735

Cited by 18 publications

(6 citation statements)

References 172 publications

(284 reference statements)

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“…The results from X‐ray analysis agree with other observations made so far about LOX as a versatile biocatalyst for biotransformation of endobiotics and xenobiotics (see review articles8, 37). It might also provide some hints as to why the kinetic studies of LOX‐3 inhibition by quercetin38 show competitive and linear behavior on a Lineweaver–Burke plot, but only to a ∼2 μ M concentration, and at 2.5 μ M it becomes nonlinear.…”

Section: Resultssupporting

confidence: 88%

Lipoxygenase interactions with natural flavonoid, quercetin, reveal a complex with protocatechuic acid in its X‐ray structure at 2.1 Å resolution

et al. 2003

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PUFA metabolites have a profound effect on inflammatory diseases and cancer progression. Blocking their production by inhibiting PUFA metabolizing enzymes (dioxygenases: cyclooxygenases and LOXs) might be a successful way to control and relieve such problems, if we learn to better understand their actions at a molecular level. Compounds with strong antioxidative and free radical scavenging properties, such as polyphenols, could be effective in blocking PUFA activities, and natural flavonoids possess such qualities. Quercetin belongs to the group of natural catecholic compounds and is known as a potent, competitive inhibitor of LOX. Structural analysis reveals that quercetin entrapped within LOX undergoes degradation, and the resulting compound has been identified by X-ray analysis as protocatechuic acid (3,4-dihydroxybenzoic acid) positioned near the iron site. Its C3-OH group points toward His523, C4-OH forms a hydrogen bond with O=C from the enzyme's C-terminus, and the carboxylic group is incorporated into the hydrogen bonding network of the active-site neighborhood via Gln514. This unexpected result, together with our previous observations concerning other polyphenols, yields new evidence about the metabolism of natural flavonoids. These compounds might be vulnerable to the co-oxidase activity of LOX, leading to enzyme-stimulated oxidative degradation, which results in an inhibitor of a lower molecular weight.

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Section: Resultssupporting

confidence: 88%

Lipoxygenase interactions with natural flavonoid, quercetin, reveal a complex with protocatechuic acid in its X‐ray structure at 2.1 Å resolution

et al. 2003

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“…This activity may be increased if hydroperoxide fatty acid is substituted by H 2 O 2 . The co‐oxidation of hydrogen donors, drugs, mutagens, carcinogens, pesticides and several chemicals by lipoxygenases from different sources has been established, and the possibility that xenobiotic oxidation mediated by lipoxygenase may occur at biologically significant rates has been suggested [2].…”

Section: Introductionmentioning

confidence: 99%

Chlorpromazine oxidation by hydroperoxidase activity of covalent immobilized lipoxygenase

Santano

Pinto

Macı́as

2002

Biotech and App Biochem

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The application of the hydroperoxidase activity of immobilized lipoxygenase to xenobiotic metabolization is reported in this work. Soya bean lipoxygenase has been immobilized by covalent coupling to oxirane acrylic beads. This immobilized system has been applied to the oxidation of chlorpromazine (CPZ), a phenothiazine of wide pharmacological use which in some cases presents toxicity. Immobilized lipoxygenase produces the oxidation of CPZ in the presence of hydrogen peroxide at acidic pH, maintaining a high level of activity and stability. In comparison with free lipoxygenase, the immobilized enzyme system shows higher catalytic efficiency and protection against enzymic inactivation produced by the presence of H(2)O(2). When the system of immobilized enzyme was loaded into a bioreactor operating in continuous mode, the level of CPZ oxidation was higher than obtained using a discontinuous procedure or the free enzyme. The results obtained in this work suggest that a system of covalent immobilized lipoxygenase operating in continuous mode may constitute a valuable tool for xenobiotic detoxification or metabolization studies.

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“…PGS is present in high concentrations in the kidney (Moldéus et al, 1982;Potter and Hinson, 1987b;Lock and Reed, 1998). Immunohistochemical localization studies have also revealed the presence of PGS in high activity in mouse embryos (Parman et al, 1999;Kulkarni, 2001).…”

Section: Discussionmentioning

confidence: 99%

In Vitro Metabolic Activation of Thiabendazole via 5-Hydroxythiabendazole: Identification of a Glutathione Conjugate of 5-Hydroxythiabendazole

Dalvie¹,

Smith²,

Deese³

et al. 2006

Drug Metab Dispos

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Thiabendazole (TBZ) (Fig. 1) is a broad-spectrum antihelmintic used for treatment of parasitic infections in animals and humans and an agricultural fungicide for postharvest treatment of fruits and vegetables (Walton et al., 1999;Groten et al., 2000). It is recognized as a potent nephrotoxin that causes tubular necrosis, leading to severe kidney damage and a teratogen that results in impairment of mouse limb development and selective toxicity to the embryo (Ogata et al., 1984;Mizutani et al., 1990;Tada et al., 1992;Fujitani et al., 1999). Irreversible binding of TBZ-related radioactivity to macromolecules and tissue protein in the mouse embryo has also been observed after oral dosing of [ 14 C]TBZ to pregnant mice (Yoneyama and Ichikawa, 1986). In humans, several isolated cases of hepatotoxicity, such as intrahepatic cholestasis or micronodular cirrhosis, have also been reported after TBZ administration (Manivel et al., 1987;Bion et al., 1995). It is currently believed that TBZ-induced nephrotoxicity is a result of P450-dependent oxidative cleavage of the thiazole moiety in TBZ to a proximate toxicant, thioformamide ( Fig. 1) (Mizutani et al., 1994). However, the mechanisms responsible for TBZ-induced hepatotoxicity in humans and teratogenicity in preclinical species are not clear.TBZ is extensively metabolized in animals and humans (Tocco et al., 1966). The primary route of metabolism is the CYP1A2-catalyzed formation of 5-hydroxythiabendazole (5-OHTBZ), which is further converted to a glucuronide and a sulfate conjugate and is eliminated in the urine and bile (Wilson et al., 1973;Rey-Grobellet et al., 1996; Coulet et al., 1998a,b). Other metabolites such as 4-hydroxythiabendazole, 2-acetylbenzimidazole, N-methylthiabendazole, and benzimidazole have also been detected (Fujitani et al., 1991). Recent studies by Coulet et al. (2000) have shown good correlation in the covalent binding of the radiolabel to proteins and the formation of 5-OHTBZ in incubations of [ 14 C]TBZ with cultured human and rabbit hepatocytes. These studies have also shown that treatment of CYP1A2-expressing liver cells with isolated [14 C]5-OHTBZ leads to significant covalent binding of the radiolabel (Coulet et al., 2000). Furthermore, 5-OHTBZ has been described to possess the same teratogenic potential as the parent drug TBZ, as demonstrated in a limb-bud culture system (Tsuchiya et al., 1987

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Role of Biotransformation in Conceptal Toxicity of Drugs and Other Chemicals

Cited by 18 publications

References 172 publications

Lipoxygenase interactions with natural flavonoid, quercetin, reveal a complex with protocatechuic acid in its X‐ray structure at 2.1 Å resolution

Lipoxygenase interactions with natural flavonoid, quercetin, reveal a complex with protocatechuic acid in its X‐ray structure at 2.1 Å resolution

Chlorpromazine oxidation by hydroperoxidase activity of covalent immobilized lipoxygenase

In Vitro Metabolic Activation of Thiabendazole via 5-Hydroxythiabendazole: Identification of a Glutathione Conjugate of 5-Hydroxythiabendazole

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