Alterations of microsomal monooxygenase system and carcinogen metabolism by streptozotocin-induced diabetes in rats

Abstract

The effects of diabetes on the liver microsomal monooxygenase enzymes and carcinogen metabolism have been studied in rats. Treatment with streptozotocin causes a marked enhancement in microsomal N-nitrosodimethylamine (NDMA) demethylase activity. The enhancement is due mainly to the induction of a high affinity NDMA demethylase (Km, approximately 0.05 mM) which is accompanied by the induction of a protein species with mol. wt. of 50,000. The treatment also induces aniline hydroxylase whose activity is in parallel with NDMA demethylase. Streptozotocin-induced diabetes also increases the metabolism of N-nitrosomethylethylamine but not that of N-nitrosomethylaniline or N-nitrosomethylbenzylamine. On the other hand, diabetes decreases the metabolism of benzo[a]pyrene, benzphetamine, and ethylmorphine. The result suggest that diabetes causes an alteration of the composition of cytochrome P-450 isozymes; the forms efficient in metabolizing NDMA are increased while certain other forms of cytochrome P-450 are decreased.

A single major gene controls most of the difference in susceptibility to streptozotocin-induced diabetes between C57BL/6J and C3H/HeJ mice

“…If SZ exerts its cytotoxic action on pancreatic B cells by lowering intracellular levels of NAD through SZ-induced activation of poly (ADP-ribose) synthetase [30][31][32][33], then the SZ-sensitivity locus may code for different alleles for this enzyme. On the other hand, allelic differences in metabolism of nitrosurea compounds may be linked to cytochrome p450 genes in mice [34][35][36]. Genetic analysis with cloned gene probes for these loci will define the relationship of these loci to SZ-induced diabetes in mice.…”

Glutathione S-transferases and chloroform toxicity in streptozotocin-induced diabetic rats.

“…Serum glucose levels in the chronic diabetic and insulin-treated rats were 582.2±31. 4 and 145.5±6.3 mg/dl, re spectively. These results indicate that the diabetic state caused by streptozotocin was normalized by insulin treatment.…”

NicotinamideN-Oxidation by CYP2E1 in Human Liver Microsomes

“…Thus, variation in CYP2E1 activity might predispose individuals to toxicity due to environmental pollutants, and numerous reports have attempted to correlate genotypic variations in CYP2E1 with various cancers (Neafsey et al, 2009). These studies suffer from limitations because the expression and the activity of CYP2E1 are also influenced by a disease state and are under nutritional control (Peng et al, 1983;Gonzalez et al, 1991;Chalasani et al, 2003). A more direct approach would involve the use of a biomarker to estimate CYP2E1 activity.…”