Inhibition of dietary mutagen activation by methylxanthines

The investigation of the link between diet and cancer in man has resulted in the identification of a variety of carcinogenic and mutagenic principles in food, particularly cooked meat (Furihata & Matsushima, 1986), the most mutagenic of these compounds being the amino-imidazoaza-arenes:2amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), 2amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (DiMeIQx), 2-amino-3-methylimidazo[4,S-f]quinoline (IQ) and 2-amino3,4-dimethylimidazo[4,5-f]quinoline (MeIQ) which collectively account for approximately half of the mutagenicity of fried beef (Felton et al., 1986). Since these compounds are all promutagens, interindividual variation in the capacity to activate them could be a determinant of the risk of developing cancer upon exposure. This activation is thought to occur mainly by the microsomal cytochrome I-’-450-dependent mono-oxygenase system. The activation of these mutagens by rat microsomes in the Ames Salmonella mutagenicity assay (the Ames test) is increased by up to 30-fold by prior treatment of the animals with polycylic aromatic hydrocarbons (PAH) such as 3-methylcholanthrene (3MC). Recent evidence suggests that of the two major isoenzymes of cytochrome P-450 induced by PAH, rat P-450d is at least partly responsible for the activation of MeIQx (Gooderham et al., 1987). The orthologous isoenzyme in man is known to be induced by cigarette smoking (Sesardic et al., 1987). PAH-inducible cytochrome P-450 is also involved in the metabolism of the widely used methylxanthines (MX) caffeine and theophylline (Campbell et al., 1987). Thus, there is a potential for interaction between these compounds and the activation of the dietary mutagens. This was investigated in the Ames test in vitro. Additionally, furafylline, an MX developed as an alternative to theophylline and known to be a potent inhibitor of caffeine metabolism in man in vivo (Tarrus et al., 1987) is also of interest, as it could be of value in the study of mutagen metabolism in man should it selectively inhibit the activation process. Hepatic microsomal fractions were prepared from male Wistar rats treated with 3MC (i.p. 80 mg/kg) in corn oil 4 8 h before killing and from human renal transplant donors. Local Research Ethics Committee permission and Coroner’s approval were obtained to use human liver samples in these studies. Mutagenicity of the four compounds was assessed by an adaption of the Ames test (strain TA98). Microsomes