Abstract
Sulphate ester and glucuronic acid conjugations are major pathways of Phase 2 drug metabolism. Their comparative study, in normal and tumour tissues, was undertaken, using various in vitro systems. The major xenobiotic used was 1-naphthol, its conjugation by UDP-glucuronosyl-transferase and sulphotransferase to 1-naphthyl-beta-D-glucuronide and 1-naphthyl sulphate respectively, being investigated. Normal human lung and colon tissue in short-term organ culture formed more 1-naphthyl sulphate, whereas tumours from these organs produced more 1-naphthyl-beta-D-glucuronide, there being a change in conjugation pathways from normal to tumour tissue. Such biochemical differences in human tissues could be exploitable in cancer chemotherapy. Possible reasons for this shift in metabolism include: changes in enzyme protein; availability of cofactors; alterations in hydrolysing enzymes. It may even be connected to alterations in cell-surface glycosaminoglycans. Normal peripheral human lung in organ culture formed almost exclusively 1-naphthyl sulphate, whereas tumour tissue from squamous carcinomas gave predominantly 1-naphthyl-beta-D-glucuronide. Normal colon produced a different pattern of conjugation from colorectal tumours. Subcellular fractions, from lung specimens, reflected the metabolism seen in culture, while those from colonic samples did not. Human bronchial carcinoma cell lines, but not those from human colon adenocarcinomas, generally produced a conjugation pattern suggesting a reasonable model for surgical tumour samples in culture. Xenografts derived from human lung and colon tumours gave a similar conjugation pattern as surgical samples in culture. Species differences occurred with short-term organ cultures from normal rodent lung and colon tissues, which produced conjugation patterns unlike those obtained from normal human tissues. For these pathways, rodent tissues would provide unsatisfactory models for humans. These results emphasised the difficulties in extrapolating from animal data to man and the importance of studying human tissues. Thus, using organ culture of human tissue, improved understanding of human metabolism, target organ toxicity and individualising treatment by testing chemosensitivity of drugs may be obtained.