IUBMB Life, 54: 357–364, 2002 Copyright c  2002 IUBMB 1521-6543/02 $12.00 + .00 DOI: 10.1080/15216540290114720 Research Communication Mood-Enhancing Antidepressant St. John’s Wort Inhibits the Activation of Human Immunodeficiency Virus Gene Expression by Ultraviolet Light Mohiuddin M. Taher, 1 Guido M. Lammering, 2 Chad M. Hershey, 3 and Kristoffer C. Valerie 3 1 Departments of Neurology and Anatomy and Neurobiology, Virginia Commonwealth University, Richmond, Virginia 2 Department of Radiation Oncology, Heinrich-Heine University D¨ usseldorf, D¨ usseldorf, Germany 3 Department of Radiation Oncology, Virginia Commonwealth University, Richmond, Virginia Summary Ultraviolet (UV) radiation is a potent activator of the human im- munodeficiency virus (HIV) gene expression in a HeLa cell clone with stably integrated copies of the HIVcat reporter construct. Re- cently, we have shown that activation of p38 MAP kinase and NF- κB is necessary but not sufficient for triggering efficient HIV gene expression in response to UV. Here we demonstrate that St. John’s wort is a potent inhibitor of the UV-induced activation of HIV gene expression in HeLa cells. Stably transfected HIVcat/HeLa cells were preincubated with different amounts (25–100 μl) of St. John’s wort or gingko biloba extracts for 30 min, then irradiated with UV (30 J/m 2 ). In contrast to ginkgo biloba, St. John’s wort inhibited the UV-induced HIV gene expression in a dose-dependent man- ner. Furthermore, preincubation with St. John’s wort (10, 20, and 30 μl) for 30 min before UV (30 J/m 2 ) irradiation, PMA- and UV- induced NF-κB activation was completely blocked, whereas ginkgo biloba did not affect the PMA- and UV-induced NF-κB activation in HeLa cells. UV activation of p38 MAP kinase was not inhibited by St. John’s wort or by ginkgo biloba. However, we found that p38 MAP kinase and JNK1 and -2 were activated by St. John’s wort, but p44/42 MAP kinase was not activated by St. John’s wort in HeLa cells. Hypericin an active ingredient in St. John’s wort also inhib- ited the UV activation of HIV gene expression in HeLa cells. These results firmly confirm that St. John’s wort is a potent inhibitor of the UV-induced activation of HIV gene expression in HeLa cells. IUBMB Life, 54: 357–364, 2002 Keywords HeLa cells; herbal medicine; hypericin; NF-κ B; signal transduction; transcription. Received 28 September 2002; accepted 21 October 2002. Address correspondence to Mohiuddin M. Taher, P. O. Box 980599, Virginia Commonwealth University, Richmond, VA 23298. Fax: 804- 828-6432; E-mail: mtaher@mail2.vcu.edu INTRODUCTION Peoplehave been ingesting St. John’s wort (SJW 1 ), a yellow-flowered plant with the Latin name, Hypericum perfo- ratum for some 2,000 years (1). St. John’s wort is widely used as a natural, herbal alternative for the treatment of depression in cases where standard antidepressants would be prescribed. St. John’s wort extracts are as effective as commonly prescribed an- tidepressants, such as Prozac, Serzone, Paxil, Zoloft, and many others, in mild-to-moderate depression and it is used in Europe and is by far the most popular antidepressant in countries such as Germany (1, 2). Promising results have been reported from a number of controlled studies on the antidepressant effects of SJW (3); however, the cellular and molecular mechanisms of these herbal remedies including SJW has yet to be elucidated (4). Physicians need more training in herbal medicine, and more research on these remedies is needed. Doctors in some European countries are trained in herbal remedies, whereas such training is rare in the United States because the basic mechanisms of action and side effects of these drugs are not well documented in the literature. Herbal medicines are a $4 billion-a-year industry in the United States and an estimated one-third of the adult popula- tion uses them (5). These remedies are sold as food supplements and not as regulated drugs. Although the herbal remedies are considered ‘natural’ products that may have benefits, adverse 1 Abbreviations: CAT, chloramphenicol acetyltransferase; EMSA, elec- trophoretic mobility shift assay; Ginkgo, ginkgo biloba; HIV, human immu- nodeficiency virus; HIVcat, cat gene under control of the HIV promoter; JNK, c-Jun-NH 2 terminal kinase; MAP, mitogen-activated protein; MKK/MEK, MAP kinase kinase; PARP, poly-ADP ribose polymerase; PKC, protein kinase C; PMA, phorbol-12-myristate 13-acetate; SJW, St. John’s wort; TNF-α, tumor necrosis factor-α; UV, ultraviolet radiation. 357