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: surh@plaza.snu.ac.kr

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

1 Reimund J-M, Allison AC, Muller CD, et al. Antioxidantsinhibit the in vitro production of inflammatory cytokines inCrohn’s disease and ulcerative colitis. Eur J Clin Invest1998;28:145–50.

2 Peristeris P, Clark BD, Gatti S, et al. N-Acetylcysteine andglutathione as inhibitors of tumor necrosis factor production.Cell Immunol 1992;140:390–9.

3 Chaudhri G, Clark IA. Reactive oxygen species facilitate thein vitro and in vivo lipopolysaccharide-induced release oftumor necrosis factor. J Immunol 1989;143:1290–4.

4 Eugui EM, DeLustro B, Rouhafza S, et al. Some antioxidantsinhibit, in a coordinate fashion, the production of tumornecrosis factor-a, IL-b, and IL-6 by human peripheral bloodmononuclear cells. Int Immunol 1994;6:409–22.

5 Davis VE, Walsh MJ. Alcohol, amines, and alkaloids: apossible biochemical basis for alcohol addiction. Science1970;167:1005–7.

6 Sourkes TL. Possible new metabolites mediating actions ofL-DOPA. Nature 1971;22:413–4.

7 Sandler M, Carter SB, Hunter KR, Stern GM.Tetrahydroisoquinoline alkaloids: in vivo metabolites ofL-Dopa in man. Nature 1973;241:439–43.

8 Matsubara K, Fukushima S, Akane A, Kobayashi S, ShionoH. Increased urinary morphine, codeine andtetrahydropapaveroline in Parkinsonian patient undergoingL-3,4-dihydroxyphenylalanine therapy: a possible biosyn-thetic pathway of morphine from L-3,4–dihydroxyphenylala-nine in humans. J Pharmacol Exp Ther 1992;260:974–8.

9 Turner AJ, Baker KM, Algeri S, Frigerio A, Garattini S.Tetrahydropapaveroline: formation in vivo and in vitro in ratbrain. Life Sci 1974;14:2247–57.

10 Cashaw JL. Tetrahydropapaveroline in brain regions of ratsafter acute ethanol administration. Alcohol 1993;10:133–8.

11 Mosca L, Blarzino C, Coccia R, Foppoli C, Rosei MA.Melanins from tetrahydroisoquinolines: spectroscopiccharacteristics, scavenging activity and redox transferproperties. Free Rad Biol Med 1998;24:161–7.

12 Rosei MA, Mosca L. Production of melanin pigments bychemical and enzymatic oxidation of tetrahydropapaveroline.Biochem Mol Biol Int 1995;35:1253–9.

13 Maruyama W, Dostert P, Naoi M. Dopamine-derived1-methyl-6,7–dihydroxyisoquinolines as hydroxyl radicalpromoters and scavengers in the rat brain: in vivo and in vitrostudies. J Neurochem 1995;54:2635–43.

14 Collins MA. A possible neurochemical mechanism for brainand nerve damage associated with chronic alcoholism. TrendsPharmacol Sci 1982;3:373–5.

15 Suzuki K, Mizuno Y, Yoshida M. Inhibition of mitochondrialrespiration by 1,2,3,4–tetrahydroisoquinoline–likeendogenous alkaloids in mouse brain. Neurochem Res1990;15:705–10.

16 Okada T, Shimada S, Sato K, et al. Tetrahydropapaverolineand its derivatives inhibit dopamine uptake throughdopamine transporter expressed in HEK293 cells. NeurosciRes 1998;30:87–90.