Decreased hepatic drug metabolising enzyme activity in rats with nitrosamine-induced tumours.
N-Methyl N-benzyl nitrosamine (MBNA), which requires P450-dependant activation to be mutagenic, has been shown to produce squamous cell carcinoma of rat oesophagus. The aim of this study was to determine the effects of tumour induction on hepatic cytochrome P450 (CYP) and phase II enzyme activity. Female Wistar rats were given MBNA (2.5 mg/kg) by gavage, twice weekly for 12 weeks. At the end of 12 weeks they were sacrificed; livers and oesophagi were removed. The activity of hepatic CYP and phase II enzymes was determined by incubation of liver microsomes with appropriate CYP substrates. All rats receiving MBNA developed oesophageal lesions. Hepatic CYP1A2 activity (phenacetin 5 microM) in tumour-bearing rats was significantly decreased to 53% of the controls (p <0.05). CYP2E1 (p-nitrophenol hydroxylase), CYP2D (debrisoquine hydroxylase) and CYP3A (quinine hydroxylase) activity was significantly (p <0.05) reduced. Microsomal UDP-glucuronosyl transferase activity was also found to be markedly decreased while glutathione-S-transferase activity remained almost unchanged. Alteration of the activities of drug metabolising enzymes in rats with chemically induced tumours could be an important factor in determining resistance or susceptibility to xenobiotics and antitumour drugs.
Maliakal
P P
PP
School of Pharmacy, University of Otago, Dunedin, New Zealand.
Coville
P F
PF
Wanwimolruk
S
S
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000187:drug effects / Q000378:metabolism; D002273:Carcinogens / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology; D019388:Cytochrome P-450 CYP1A2 / Q000187:drug effects / Q000378:metabolism; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D019392:Cytochrome P-450 CYP2E1 / Q000187:drug effects / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects* / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004938:Esophageal Neoplasms / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology; D005260:Female; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D009602:Nitrosamines / Q000494:pharmacology*; D009928:Organ Specificity; D010089:Oxidoreductases, N-Demethylating / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
D002273:Carcinogens; D009602:Nitrosamines; D003577:Cytochrome P-450 Enzyme System; D019392:Cytochrome P-450 CYP2E1; D001189:Aryl Hydrocarbon Hydroxylases; D019388:Cytochrome P-450 CYP1A2; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; C468271:N-methyl-N-benzylnitrosamine