Mechanism of toxicity of the antimelanoma drug 4-hydroxyanisole in mouse hepatocytes

Schiller, Claus D.; Gescher, Andreas; Jheeta, Parmjit

doi:10.1016/0277-5379(91)90272-f

Cited by 8 publications

(5 citation statements)

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“…Previously, it was reported that ring hydroxylation of 4-HA was not a bioactivation route because 3,4-diacetoxyanisole, a prodrug of the metabolite 4-methoxycatechol, which forms if 4-HA undergoes ring hydroxylation, was not more toxic than 4-HA (Schiller et al, 1991). Further mechanistic studies showed that incubation of 4-HA with rat liver microsomes (Cheeseman, 1984) or mouse liver microsomes (Schiller et al, 1991) produced little formaldehyde, indicating that O-demethylation of 4-HA to HQ was not a major metabolic pathway. However, they speculated that the cytotoxic metabolite of 4-HA was probably an epoxide without elucidating its chemical structure or identifying a GSH conjugate (Schiller et al, 1991).…”

Section: Discussionmentioning

confidence: 99%

“…Further mechanistic studies showed that incubation of 4-HA with rat liver microsomes (Cheeseman, 1984) or mouse liver microsomes (Schiller et al, 1991) produced little formaldehyde, indicating that O-demethylation of 4-HA to HQ was not a major metabolic pathway. However, they speculated that the cytotoxic metabolite of 4-HA was probably an epoxide without elucidating its chemical structure or identifying a GSH conjugate (Schiller et al, 1991).…”

Section: Discussionmentioning

confidence: 99%

“…However, other mechanistic studies showed that incubation of 4-HA with rat liver microsomes (Cheeseman, 1984) and mouse liver microsomes (Schiller et al, 1991) produced little formaldehyde, suggesting that O-demethylation of 4-HA to HQ was not a major metabolic pathway. Furthermore, 3,4-diacetoxyanisole, a prodrug of 4-methoxycatechol, was not more toxic than 4-HA toward mouse hepatocytes, indicating that this possible ring hydroxylation metabolite of 4-HA also did not account for its cytotoxicity (Schiller et al, 1991).In the current work, we have sought to test the validity of these findings by investigating the P450-mediated bioactivation of 4-HA and HQ in isolated rat hepatocytes. It was found that ring epoxidation and/or one electron oxidation rather than O-demethylation/ring hydroxylation/ipso attack was the bioactivation route for 4-HA in rat liver.…”

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Metabolic Activation of 4-Hydroxyanisole by Isolated Rat Hepatocytes

Moridani

Cheon²,

Khan³

et al. 2002

Drug Metab Dispos

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This article is available online at http://dmd.aspetjournals.org ABSTRACT:A tyrosinase-directed therapeutic approach for treating malignant melanoma uses depigmenting phenolic prodrugs such as 4-hydroxyanisole (4-HA) for oxidation by melanoma tyrosinase to form cytotoxic o-quinones. However, in a recent clinical trial, both renal and hepatic toxicity were reported as side effects of 4-HA therapy. In the following, 4-HA (200 mg/kg i.p.) administered to mice caused a 7-fold increase in plasma transaminase toxicity, an indication of liver toxicity. Furthermore, 4-HA induced-cytotoxicity toward isolated hepatocytes was preceded by glutathione (GSH) depletion, which was prevented by cytochrome P450 inhibitors that also partly prevented cytotoxicity. The 4-HA metabolite formed by NADPH/microsomes and GSH was identified as a hydroquinone mono-glutathione conjugate. GSH-depleted hepatocytes were much more prone to cytotoxicity induced by 4-HA or its reactive metabolite hydroquinone (HQ). Dicumarol (an NAD(P)H/quinone oxidoreductase inhibitor) also potentiated 4-HA-or HQ-induced toxicity whereas sorbitol, an NADH-generating nutrient, prevented the cytotoxicity. Ethylenediamine (an o-quinone trap) did not prevent 4-HA-induced cytotoxicity, which suggests that the cytotoxicity was not caused by o-quinone as a result of 4-HA ring hydroxylation. Deferoxamine and the antioxidant pyrogallol/4-hydroxy-2,2,6,6-tetramethylpiperidene-1-oxyl (TEMPOL) did not prevent 4-HA-induced cytotoxicity, therefore excluding oxidative stress as a cytotoxic mechanism for 4-HA. A negligible amount of formaldehyde was formed when 4-HA was incubated with rat microsomal/ NADPH. These results suggest that the 4-HA cytotoxic mechanism involves alkylation of cellular proteins by 4-HA epoxide or p-quinone rather than involving oxidative stress.The incidence of malignant melanoma is increasing at an alarming rate among Caucasians (Albino and Fountain, 1993). The lack of effective antimelanoma drugs for treating this form of cancer is partly due to drug resistance (Nathanson and Jilani, 1993). Metastatic melanoma cells are pigmented because active tyrosinase of the melaninsynthesizing pathway is found in melanocytes (Riley, 1991). Thus, the unique ability of melanocytes to produce melanin pigment could be exploited in an enzyme directed melanoma therapy (Jimbow et al., 1993). The selective toxicity of phenolic antimelanoma agents toward local and metastatic melanoma cells could be achieved if the phenolic agent were bioactivated by melanoma tyrosinase to form reactive o-quinones as long as the agent was not bioactivated by hepatic or renal cytochrome P450. Several phenolic agents have been tested for their antimelanoma effect among which 4-hydroxyanisole (4-HA 1 ) had the greatest depigmenting ability. 4-HA was first shown by Riley (1969) to be a melanocytotoxic agent. Depigmentation and tumor shrinkage resulted from both the topical application of 4-HA (Riley, 1969) and intra-arterial infusions of 4-HA into the legs (Morgan, 1984). Unfortunately, 4-HA cl...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Metabolic Activation of 4-Hydroxyanisole by Isolated Rat Hepatocytes

Moridani

Cheon²,

Khan³

et al. 2002

Drug Metab Dispos

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“…The discovery that certain substituted phenols have a depigmenting action due to their ability to act as substrates for tyrosinase, resulting in the generation of quinones, has led to the examination of this system as a possible targeted antimelanoma therapeutic strategy in the case of disseminated melanoma [76][77][78][79]. For such a chemotherapeutic agent to be useful, the prodrug must evade hepatic metabolism and other potentially toxic reactions [80,81], reach the tumor tissue and enter the malignant melanocytes. Moreover, this prodrug has to avoid alternative cellular metabolism and enter melanosomes, leading to oxidation by tyrosinase to generate significant amounts of the quinone product, which requires the ability to initiate reactions damaging to the melanoma cell.…”

Section: Tyrosinase Inhibitorsmentioning

confidence: 99%

Tyrosinase inhibitors from natural and synthetic sources: structure, inhibition mechanism and perspective for the future

Kim

Uyama

2005

CMLS, Cell. Mol. Life Sci.

936

674

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Tyrosinase is known to be a key enzyme in melanin biosynthesis, involved in determining the color of mammalian skin and hair. Various dermatological disorders, such as melasma, age spots and sites of actinic damage, arise from the accumulation of an excessive level of epidermal pigmentation. In addition, unfavorable enzymatic browning of plant-derived foods by tyrosinase causes a decrease in nutritional quality and economic loss of food products. The inadequacy of current conventional techniques to prevent tyrosinase action encourages us to seek new potent tyrosinase inhibitors. This article overviews the various inhibitors obtained from natural and synthetic sources with their industrial importance.

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Tyrosinase‐Mediated Cytotoxicity of 4‐Substituted Phenols: Use of QSAR to Forecast Reactivities of Thiols towards the Derivedortho‐Quinones

Cooksey

Land

Rushton

et al. 1996

Quant. Struct.‐Act. Relat.

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Certain 4-substituted phenols can behave as tyrosine analogues and undergo tyrosinase-catalysed oxidation to cytotoxic o-quinones which react with crucial cellular thiols. Such phenols are potential melanogenesis-specific pro-drugs for the chemotherapy of malignant melanoma. Previously (Cooksey er al. (1995) Anti-Cancer Drug Design, 10, I19), by pulse radiolysis under oxidative conditions of the corresponding stable catechols in the presence and absence of thiols, we showed that the glutathione and cysteine reactivities of ten 4-substituted o-quinones correlated well with the Hammett cP constants of the corresponding substituents. Starting from the corresponding catechols, one of which has not previously been described, we have now investigated six further 4-substituted o-quinones including two with substituent crp values higher than those previously studied. Extrapolation of the earlier quantitative structure -activity relationships (QSAR) correctly predicted the high reactivities of these two o-quinones, with respective substituents OCF, and CH,NH,+, towards thiols. The data for all sixteen 4-substituted o-quinones, and for o-benzoquinone itself, have been combined to provide updated, statistically significant Hammett and Swain-Lupton correlations, including multivariate regressions using the data for both thiols. These relationships show that in reacting the substituted o-quinones with thiols, the rate constants increase with the electron withdrawing capacities of the substituent groups, this being principally due to the resonance effect, with a smaller but significant contribution attributable to the field effect. Such QSAR may facilitate the design of improved melanogenesis -targeted anti-melanoma pro-drugs.

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Mechanism of toxicity of the antimelanoma drug 4-hydroxyanisole in mouse hepatocytes

Cited by 8 publications

References 20 publications

Metabolic Activation of 4-Hydroxyanisole by Isolated Rat Hepatocytes

Metabolic Activation of 4-Hydroxyanisole by Isolated Rat Hepatocytes

Tyrosinase inhibitors from natural and synthetic sources: structure, inhibition mechanism and perspective for the future

Tyrosinase‐Mediated Cytotoxicity of 4‐Substituted Phenols: Use of QSAR to Forecast Reactivities of Thiols towards the Derivedortho‐Quinones

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