Tetrahydropapaveroline, a dopamine-derived isoquinoline alkaloid, undergoes oxidation: implications...
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European Journal of Clinical Investigation (1999) 29, 650–651 Letter to the Editor Tetrahydropapaveroline, a dopamine-derived isoquinoline alkaloid, undergoes oxidation: implications for DNA damage and neuronal cell death Y.-J. Surh Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Shinlim-dong, Kwanak-gu, Seoul 151-742, Korea Sir, I read with interest the paper by Reimund et al. [1], which focused on the inhibitory effects of butylated hydroxyani- sole (BHA), nordihydroguaiaretic acid (NDGA) and tetra- hydropapaveroline (THP) on production of inflammatory cytokines in Crohn’s disease and ulcerative colitis. In concluding their work, the authors stated that several antioxidants, including BHA, NDGA and THP, inhibited to some extent cytokine production in cultured peripheral blood mononuclear cells and in organ cultures of colonic mucosa from Crohn’s disease and ulcerative colitis patients. There is compelling evidence supporting the role of reactive oxygen intermediates (ROIs) as potential effector molecules in mediating the inflammation cascade. As noted by the authors, some antioxidants have been reported to suppress the production of proinflammatory cytokines, such as tumour necrosis factor a and inter- leukins [2,3]. In line with these previous findings, the authors appeared to select BHA, NDGA and THP as candidate antioxidants to evaluate their anti-inflammatory potential in terms of suppressing cytokine production in cultured target organs from patients suffering from inflam- matory bowel diseases. All of these compounds have been reported by other investigators to inhibit the production of selected proinflammatory cytokines by suppression of nuclear factor (NF)-kB activation [3,4]. BHA is an artificial antioxidant used as a food additive, and NDGA is a phytochemical with pronounced inhibitory effects on 5-lipoxygenase. There is no doubt that these two sub- stances are among representative antioxidants. In contrast, THP is not generally accepted as an antioxidant, but it may rather act as a pro-oxidant. THP is a benzyliso- quinoline alkaloid synthesized in animals as well as in plants by Pictet–Spengler condensation of dopamine with its own deaminated product, 3,4-dihydroxyphenyl- acetaldehyde (dopaldehyde) [5,6]. This tetrahydroiso- quinoline catechol has been detected in the urine of Parkinsonian patients on 3,4-dihydroxyphenylalanine (L-DOPA) medication [6–8] and its levels in urine and brain of rats increase after treatment with L-DOPA [9] or ethanol [5,10]. Several recent studies have revealed that THP is readily oxidized by peroxidase, lipoxygenase or xanthine oxidase [11] and also by tyrosinase [12]. The oxidation of THP leads to formation of a melanin-like pigment [11,12]. The relatively high levels of ROIs, such as hydrogen peroxide and superoxide, in the tissues undergoing inflammatory pro- cesses would facilitate the oxidation of THP to semiquinone and further to quinone products, particularly in the presence of oxidases as demonstrated previously [11]. Although quinoidal forms of THP are anticipated to be reactive per se, they can be converted back to the parent catechol, with concomitant production of ROIs capable of damaging cri- tical cellular molecules, such as DNA, RNA, protein and membrane lipid. According to a recent study in this labora- tory, THP undergoes redox cycling in the presence of certain transition metal ions such as Cu 2þ to produce ROIs, which causes DNA strand scission. The compound also exerts cytotoxicity in cultured rat phaeochromocytoma (PC12) cells, possibly by causing oxidative stress in these cells. These findings definitely indicate that THP has a pro- oxidant activity and efforts are under way in my laboratory to determine whether THP-induced cell death is associated with oxygen free radical-mediated apoptosis. Many compounds that exert pro-oxidant actions also possess antioxidant properties. For instance, L-DOPA and dopamine have been shown to have a complex mixture of pro- and antioxidant effects [13]. In this context, THP, which also bears a catechol moiety, may exert an anti- oxidant action under certain physiological conditions. Nonetheless, this tetrahydroisoquinoline catechol has relatively high redox potential and, most importantly, is Q 1999 Blackwell Science Ltd Correspondence to: Professor Y.-J. Surh, College of Pharmacy, Seoul National University, Shinlim-dong, Kwanak-gu, Seoul 151–742, South Korea. E-mail: [email protected] Received 1 March 1999; accepted 20 March 1999
Transcript of Tetrahydropapaveroline, a dopamine-derived isoquinoline alkaloid, undergoes oxidation: implications...
European Journal of Clinical Investigation (1999) 29, 650–651
Letter to the Editor
Tetrahydropapaveroline, a dopamine-derived isoquinolinealkaloid, undergoes oxidation: implications for DNAdamage and neuronal cell death
Y.-J. SurhResearch Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Shinlim-dong,Kwanak-gu, Seoul 151-742, Korea
Sir,I read with interest the paper by Reimund et al. [1], whichfocused on the inhibitory effects of butylated hydroxyani-sole (BHA), nordihydroguaiaretic acid (NDGA) and tetra-hydropapaveroline (THP) on production of inflammatorycytokines in Crohn’s disease and ulcerative colitis. Inconcluding their work, the authors stated that severalantioxidants, including BHA, NDGA and THP, inhibitedto some extent cytokine production in cultured peripheralblood mononuclear cells and in organ cultures of colonicmucosa from Crohn’s disease and ulcerative colitispatients. There is compelling evidence supporting therole of reactive oxygen intermediates (ROIs) as potentialeffector molecules in mediating the inflammation cascade.As noted by the authors, some antioxidants have beenreported to suppress the production of proinflammatorycytokines, such as tumour necrosis factor a and inter-leukins [2,3]. In line with these previous findings, theauthors appeared to select BHA, NDGA and THP ascandidate antioxidants to evaluate their anti-inflammatorypotential in terms of suppressing cytokine production incultured target organs from patients suffering from inflam-matory bowel diseases. All of these compounds have beenreported by other investigators to inhibit the production ofselected proinflammatory cytokines by suppression ofnuclear factor (NF)-kB activation [3,4]. BHA is an artificialantioxidant used as a food additive, and NDGA is aphytochemical with pronounced inhibitory effects on5-lipoxygenase. There is no doubt that these two sub-stances are among representative antioxidants. In contrast,THP is not generally accepted as an antioxidant, but itmay rather act as a pro-oxidant. THP is a benzyliso-quinoline alkaloid synthesized in animals as well as in
plants by Pictet–Spengler condensation of dopamine withits own deaminated product, 3,4-dihydroxyphenyl-acetaldehyde (dopaldehyde) [5,6]. This tetrahydroiso-quinoline catechol has been detected in the urine ofParkinsonian patients on 3,4-dihydroxyphenylalanine(L-DOPA) medication [6–8] and its levels in urine andbrain of rats increase after treatment with L-DOPA [9] orethanol [5,10].
Several recent studies have revealed that THP is readilyoxidized by peroxidase, lipoxygenase or xanthine oxidase[11] and also by tyrosinase [12]. The oxidation of THPleads to formation of a melanin-like pigment [11,12]. Therelatively high levels of ROIs, such as hydrogen peroxide andsuperoxide, in the tissues undergoing inflammatory pro-cesses would facilitate the oxidation of THP to semiquinoneand further to quinone products, particularly in the presenceof oxidases as demonstrated previously [11]. Althoughquinoidal forms of THP are anticipated to be reactive perse, they can be converted back to the parent catechol, withconcomitant production of ROIs capable of damaging cri-tical cellular molecules, such as DNA, RNA, protein andmembrane lipid. According to a recent study in this labora-tory, THP undergoes redox cycling in the presence ofcertain transition metal ions such as Cu2þ to produceROIs, which causes DNA strand scission. The compoundalso exerts cytotoxicity in cultured rat phaeochromocytoma(PC12) cells, possibly by causing oxidative stress in thesecells. These findings definitely indicate that THP has a pro-oxidant activity and efforts are under way in my laboratory todetermine whether THP-induced cell death is associatedwith oxygen free radical-mediated apoptosis.
Many compounds that exert pro-oxidant actions alsopossess antioxidant properties. For instance, L-DOPA anddopamine have been shown to have a complex mixture ofpro- and antioxidant effects [13]. In this context, THP,which also bears a catechol moiety, may exert an anti-oxidant action under certain physiological conditions.Nonetheless, this tetrahydroisoquinoline catechol hasrelatively high redox potential and, most importantly, is
Q 1999 Blackwell Science Ltd
Correspondence to: Professor Y.-J. Surh, College of Pharmacy,Seoul National University, Shinlim-dong, Kwanak-gu, Seoul151–742, South Korea. E-mail: [email protected]
Received 1 March 1999; accepted 20 March 1999
Letter to the Editor 651
Q 1999 Blackwell Science Ltd, European Journal of Clinical Investigation, 29, 650–651
likely to form highly electrophilic tautomers via oxidativeconversion to 3,4-dihydroisoquinolines (reviewed inRef. 14; see also references therein]. In addition, THPwas reported to inhibit mitochondrial respiration in mousebrain [15], and its intracerebral accumulation is thought tobe implicated in Parkinson’s disease and alcohol addiction[16]. Taking all these findings together, THP does notappear to be a proper candidate molecule to be used fordelineating the antioxidant effects on inflammatory boweldiseases as attempted by these authors [1] and others [4],and they should be cautious in including this potentiallyneurotoxic isoquinoline alkaloid as a model antioxidant forany similar investigations in the future.
Acknowledgement
This work was supported by the Academic ResearchFund (97 Genetic Engineering Grant) of the Ministry ofEducation, Republic of Korea.
References
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