Placental glutathione S-transferase (GST-P) induction as a potential mechanism for the anti-carcinogenic effect of the coffee-specific components cafestol and kahweol

The coffee specific diterpenes cafestol and kahweol (C+K) have been reported to be anti-carcinogenic in several animal models, It has been postulated that this activity may be related to their ability to induce glutathione S-transferases (GSTs). We investigated the influence of a mixture of C+K, incorporated at various levels in the diet of Sprague-Dawley rats, on the expression of different hepatic GST iso-enzymes. Liver samples were examined using isoform-specific GST substrates and antibodies, and highly selective oligomers were employed to determine effects at the RNA level. A dose-dependent increase in general GST activity was observed in male and female animals following 28 or 90 days of treatment. A time-course study demonstrated that the maximal effect was observed within 5 days of treatment, Little or no effect was found on the activity of GST alpha and mu iso-enzymes, The most striking observation was a dose-dependent induction of placental glutathione S-transferase (GST-P) which could be demonstrated at the mRNA, protein and enzymatic levels, This effect was observed in both male and female rats, The maximal induction was attained within 5 days of treatment with C+K, remained elevated with continued treatment, but was reversible on withdrawal of treatment. Immunohistochemical examination of liver slices revealed a strong even distribution of GST-P expression throughout the acinus at the highest dose of C+K, while at lower doses the induction of GST-P occurred predominantly in periportal hepatocytes. There was no indication of the presence of preneoplastic foci and, furthermore, the effect of C+K on the GST-P was completely reversible, These findings indicate that the anticarcinogenic mechanism of C+K may involve a specific induction of GST-P and suggest a potential role for GST-P in detoxifying carcinogenic compounds.