Peroxidase, an alternate pathway to cytochrome P‐450 for xenobiotic metabolism in skin: Partial purification and properties of the enzyme from neonatal rat skin

Strohm, B. H.; Kulkarni, Arun P.

doi:10.1002/jbt.2570010408

Cited by 19 publications

(10 citation statements)

References 30 publications

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“…In addition, the amount of cytochromes P450 (P450s) in the skin is limited, and this makes an arene oxide less attractive as a cause of skin rash. The skin does contain other metabolic enzymes such as peroxidases (Strohm and Kulkarni, 1986), sulfotransferases (Kudlacek et al, 1995;Higashi et al, 2004), and tyrosinase (Pomerantz and Ances, 1975;Vijayan et al, 1982;Wittbjer et al, 1991).…”

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confidence: 99%

Possible Bioactivation Pathways of Lamotrigine

Lu¹,

Uetrecht²

2007

Drug Metabolism and Disposition

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ABSTRACT:The anticonvulsant lamotrigine is associated with idiosyncratic drug reactions, especially skin rashes. Most idiosyncratic reactions are believed to be caused by reactive metabolites. Previous studies have found evidence that an arene oxide is formed in rats; however, when we incubated radiolabeled lamotrigine with rat liver microsomes virtually no covalent binding was detected, and the expected downstream phenolic metabolites are not observed in humans. Rare cases of agranulocytosis have been associated with lamotrigine therapy, and we found that lamotrigine is oxidized to two different N-chloro products by HOCl. The more reactive Nchloro metabolite forms an adduct with N-acetylhistidine, and covalent binding was observed when radiolabeled lamotrigine was incubated with myeloperoxidase/H 2 O 2 /Cl ؊ . Another lamotrigine metabolite is an N-oxide. If this N-oxide were sulfated, it might be sufficiently reactive to bind to protein. The synthetic N-sulfate reacted with N-acetylserine; however, no covalent binding was detected when the radiolabeled N-oxide was incubated with sulfotransferase. We also investigated the possibility that lamotrigine might be oxidized to a free radical by other peroxidases or oxidized by other enzymes such as prostaglandin H synthase or tyrosinase, but no evidence of oxidation was found, and lamotrigine did not cause any detectable increase in lipid peroxidation in vivo. In view of the virtual lack of covalent binding to hepatic microsomes and the lack of any other likely pathway leading to metabolic activation in the skin, it is possible that the parent drug rather than a reactive metabolite causes lamotrigine-induced skin rashes.

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confidence: 99%

Possible Bioactivation Pathways of Lamotrigine

Lu¹,

Uetrecht²

2007

Drug Metabolism and Disposition

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“…Strohm and Kulkarni (1986) found in rat skin a peroxidase activity for a large array of substrates (benzidine, 3,3′-dimethoxybenzidine, tetramethylbenzidine, p -phenylenediamine, hydroquinone, catechol, pyrogallol, para-cresol). The activity was inhibited by cyanide and by azide.…”

Section: Xenobiotica-metabolizing Enzymes In the Rat Skinmentioning

confidence: 99%

Xenobiotica-metabolizing enzymes in the skin of rat, mouse, pig, guinea pig, man, and in human skin models

2018

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Studies on the metabolic fate of medical drugs, skin care products, cosmetics and other chemicals intentionally or accidently applied to the human skin have become increasingly important in order to ascertain pharmacological effectiveness and to avoid toxicities. The use of freshly excised human skin for experimental investigations meets with ethical and practical limitations. Hence information on xenobiotic-metabolizing enzymes (XME) in the experimental systems available for pertinent studies compared with native human skin has become crucial. This review collects available information of which—taken with great caution because of the still very limited data—the most salient points are: in the skin of all animal species and skin-derived in vitro systems considered in this review cytochrome P450 (CYP)-dependent monooxygenase activities (largely responsible for initiating xenobiotica metabolism in the organ which provides most of the xenobiotica metabolism of the mammalian organism, the liver) are very low to undetectable. Quite likely other oxidative enzymes [e.g. flavin monooxygenase, COX (cooxidation by prostaglandin synthase)] will turn out to be much more important for the oxidative xenobiotic metabolism in the skin. Moreover, conjugating enzyme activities such as glutathione transferases and glucuronosyltransferases are much higher than the oxidative CYP activities. Since these conjugating enzymes are predominantly detoxifying, the skin appears to be predominantly protected against CYP-generated reactive metabolites. The following recommendations for the use of experimental animal species or human skin in vitro models may tentatively be derived from the information available to date: for dermal absorption and for skin irritation esterase activity is of special importance which in pig skin, some human cell lines and reconstructed skin models appears reasonably close to native human skin. With respect to genotoxicity and sensitization reactive-metabolite-reducing XME in primary human keratinocytes and several reconstructed human skin models appear reasonably close to human skin. For a more detailed delineation and discussion of the severe limitations see the Conclusions section in the end of this review.

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“…It is interesting to note that other tissues such as the skin, uterus, and the harderian gland (Morrison and Allen, 1966;Lyttle and De-Sombre, 1977;Strohm and Kulkarni, 1986) have been shown to possess peroxidase activity, and these tissues have been implicated as other possible sites of benzene toxicity in rodents (Huff, 1986). The presence of peroxidases in the Zymbal gland has been proposed to play an important role in the bioactivation of Zymbal gland carcinogens such as aminostilbene derivatives to reactive intermediates (Neuman et al, 1979;Osborne et al, 1980).…”

Section: Discussionmentioning

confidence: 98%

“…An extinction coefficient of 26.6 mM-' cm-' was used to quantitate the amount of tetraguaiacol formed over time. In experiments that measured peroxidase activity based on dianisidine (3,3 '-dimethoxybenzidine) as substrate, incubation conditions were similar to those used for guaiacol (Strohm and Kulkarni, 1986). The rate of change in absorbance at 470 nm was monitored and an extinction coefficient of 11.3 mM-' cm-' was used to quantitate the amount of dianisidine dimine formed.…”

Section: Peroxidase Assaymentioning

confidence: 99%

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Tissue-Specific Metabolism of Benzene in Zymbal Gland and Other Solid Tumor Target Tissues in Rats

Low

Lambert

Meeks

et al. 1995

Journal of the American College of Toxicology

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In vitro studies were carried out to investigate whether target organ susceptibility to benzene-induced solid tumor formation is governed by tissuespecific differences in metabolism. The ability of several target and nontarget tissues to deconjugate and conjugate polar metabolites, to metabolize benzene to phenolic metabolites, to carry out peroxidative biotransformations, and to trap tissue glutathione was evaluated. The Zymbal gland, the organ most sensitive to benzene-induced tumorigenicity, showed extensive phenyl-and arylsulfatase activity but no phenol sulfoconjugating activity. Similarly, oral cavity tissue, mammary gland, and bone marrow showed sulfatase activity but lacked sulfotransferase activity. Sulfatase-mediated hydrolysis such as that observed in the Zymbal gland may represent an important pathway by which polar metabolites are shunted from urinary or biliary excretion as their sulfates to delivery to target tissues as phenolic or potentially reactive metabolite(s). Zymbal gland, nasal and oral cavity, and mammary gland tissue homogenates (10,000 g supernatant) all possess oxidative capability to metabolize benzene to phenol, hydroquinone, and catechol. Nasal cavity homogenates produced twoto eightfold higher levels of phenol, hydroquinone, and catechol from benzene than did liver homogenates. Zymbal gland, bone marrow, and oral cavity homogenates, when incubated with hydroquinone and glutathione, produced high levels of 2-(S-glutathionyl)hydroquinone, indirectly indicating the production of 1 ,Cbenzoquinone, a reactive intermediate implicated in benzene toxicity.Peroxidases have been proposed to mediate the oxidation ofp-hydroquinone to 1 ,Cbenzoquinone. The Zymbal gland, nasal and oral cavities, mammary gland, and bone marrow all were found to possess greater peroxidase activity than contrasting nontarget tissues did. The metabolic capabilities of target tissues, including the ability to hydrolyze sulfate conjugates to free phenolic compounds, to oxidize benzene to phenolic metabolites, to bioactivate hydroquinone to a reactive intermediate, and to carry out peroxidative reactions may offer possible explanations for the greater susceptibility of these sites to ben-

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Peroxidase, an alternate pathway to cytochrome P‐450 for xenobiotic metabolism in skin: Partial purification and properties of the enzyme from neonatal rat skin

Cited by 19 publications

References 30 publications

Possible Bioactivation Pathways of Lamotrigine

Possible Bioactivation Pathways of Lamotrigine

Xenobiotica-metabolizing enzymes in the skin of rat, mouse, pig, guinea pig, man, and in human skin models

Tissue-Specific Metabolism of Benzene in Zymbal Gland and Other Solid Tumor Target Tissues in Rats

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