Insulin-dependent diabetes mellitus influences the metabolism of xenobiotics by modifying their rates of oxidation and subsequent conjugation with endogenous substrates. Chemically-induced diabetes increases the levels of the hepatic xenobiotic metabolising cytochrome P450 proteins belonging to the CYP1, CYP2 (subfamilies B and E), CYP3 and CYP4 families. As a result, diabetes is associated with increased susceptiblility to the toxicity of chemicals activated by the cytochrome P450 families. Similar observations have been made in spontaneously diabetic animal models such as the insulin-dependent diabetic Bio Breeding rat. In all cases, the diabetes-induced alterations of xenobiotic metabolism and chemical toxicity were successfully antagonised by insulin treatment. The altered concentrations of ketone bodies, triglycerides and growth hormone which accompany insulin-dependent diabetes appear to underlie the alterations in cytochrome P450 proteins. In contrast, alteration of drug metabolism in non-insulin-dependent diabetes mellitus, which is rarely associated with ketosis, is markedly less pronounced. However, the levels and activities of conjugating enzymes and substrates are altered which may modulate the susceptibility to chemicals that rely on these processes for their deactivation.
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