Over-expression of glutathione S-transferases, DT-diaphorase and an apparently tumour-specific cytosolic class-3 aldehyde dehydrogenase by Warthin tumours and mucoepidermoid carcinomas of the human parotid gland.
Cytosolic class-3 aldehyde dehydrogenase (ALDH-3) may help to protect organisms from certain environmental aldehydes by catalysing their detoxification. Consistent with this notion are the reports that relatively high levels of this enzyme are present in tissues, e.g. stomach mucosa and lung, that are so-called ports of entry for such agents. Further, it is found in human saliva. The present investigation revealed that small amounts of this enzyme are also present in human salivary glands; mean values for ALDH-3 activities (NADP-dependent enzyme-catalysed oxidation of benzaldehyde) in cytosolic fractions prepared from submandibular and parotid glands were 52 (range: 29-92) and 44 (range: 13-73) mIU/g tissue, respectively. Essentially identical or slightly lower levels of this enzyme activity were found in pleomorphic adenomas, an undifferentiated carcinoma, and an adenocystic carcinomas, of the parotid gland. On the other hand, Warthin tumours, and mucoepidermoid carcinomas of the parotid gland exhibited relatively elevated levels of ALDH-3 activity; mean values were 1200 (range: 780-1880) and 810 (range: 580-1200) mIU/g tissue, respectively. The ALDH-3 found in normal salivary glands was, as judged by physical, immunological and kinetic criteria, identical to human stomach mucosa ALDH-3 whereas the ALDH-3 present in Warthin tumours, and mucoepidermoid carcinomas, of the parotid gland appeared to be a subtle variant thereof. Qualitatively paralleling the relatively elevated ALDH-3 levels in mucoepidermoid carcinomas and Warthin tumours were relatively elevated levels of glutathione S-transferase (alpha and pi) and DT-diaphorase. As was the case with ALDH-3 levels, glutathione S-transferase (alpha and pi) and DT-diaphorase levels were not elevated in pleomorphic adenomas. Glutathione S-transferase mu was not detected in the two normal parotid gland samples, or in the single pleomorphic adenoma sample, tested. It was found in the single mucoepidermoid carcinoma sample, and in one of the two Warthin tumour samples tested. Cellular levels of ALDH-3, glutathione S-transferases and/or DT-diaphorase could be useful criteria when the decision to be made is whether a salivary gland tumour is a mucoepidermoid carcinoma. ALDH-3 and glutathione S-transferases are known to catalyse the detoxification of two agents that are used to treat salivary gland tumours, viz. cyclophosphamide and cisplatin, respectively. Thus, elevated levels of these enzymes in the mucoepidermoid carcinomas must account for, or at least contribute to, the relative ineffectiveness of these agents when used to treat this tumour.
Sreerama
L
L
Department of Pharmacology, University of Minnesota Medical School, Minneapolis 55455, USA.
Sladek
N E
NE
D000235:Adenolymphoma / Q000201:enzymology* / Q000235:genetics; D008949:Adenoma, Pleomorphic / Q000201:enzymology / Q000235:genetics; D000444:Aldehyde Dehydrogenase / Q000235:genetics*; D000970:Antineoplastic Agents / Q000378:metabolism / Q000627:therapeutic use; D018906:Antineoplastic Agents, Alkylating / Q000378:metabolism / Q000627:therapeutic use; D001547:Benzaldehydes / Q000378:metabolism; D002277:Carcinoma / Q000201:enzymology / Q000235:genetics; D003528:Carcinoma, Adenoid Cystic / Q000201:enzymology / Q000235:genetics; D018277:Carcinoma, Mucoepidermoid / Q000201:enzymology* / Q000235:genetics; D002945:Cisplatin / Q000378:metabolism / Q000627:therapeutic use; D003520:Cyclophosphamide / Q000378:metabolism / Q000627:therapeutic use; D003600:Cytosol / Q000201:enzymology*; D008058:Dihydrolipoamide Dehydrogenase / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005753:Gastric Mucosa / Q000201:enzymology; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D009243:NAD / Q000378:metabolism; D010306:Parotid Gland / Q000201:enzymology; D010307:Parotid Neoplasms / Q000201:enzymology* / Q000235:genetics; D013363:Submandibular Gland / Q000201:enzymology
D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; D001547:Benzaldehydes; D009243:NAD; D003520:Cyclophosphamide; D000444:Aldehyde Dehydrogenase; D008058:Dihydrolipoamide Dehydrogenase; D005982:Glutathione Transferase; D002945:Cisplatin; C032175:benzaldehyde