Cytochrome P450 1A-like proteins expressed in the islets of Langerhans and altered pancreatic beta-cell secretory responsiveness.
1. The cytochrome P450 (CYP) mixed-function oxidase system is widely distributed in body tissues and plays a key role in the metabolism of endogenous and exogenous compounds. Little attention has been paid to the expression of the system in the islets of Langerhans. The current study has examined the expression and potential role of the CYP1A family within the islets of Langerhans of control and 3-methylcholanthrene (3-MC)-induced Wistar rats. 2. CYP1A expression within pancreatic slices and islets from 3-MC-induced and control rats demonstrated that CYP1A-like protein levels were induced by 3-MC pretreatment (25 mg kg-1 day-1; i.p. for 3 days). 3. Effects of 3-MC-induction on beta-cell secretory responsiveness were investigated by use of rat collagenase-isolated islets. Insulin release from control islets incubated with 3 mM glucose (basal) was 1.4 +/- 0.2 ng/islet h-1 (mean +/- s.e.mean, n = 7). Incubation with 16.7 mM glucose, 25 mM KCl, 100 microM arachidonic acid, or 100 microM carbachol caused a 4.4, 7.0, 4.0 and 4.2 fold, respectively, increase in insulin release (P < 0.001). Forskolin (2 microM), or phorbol 12-myristic 13-acetate (10 nM) potentiated glucose-stimulated insulin release 1.2 and 1.6 fold (P < 0.01) whereas adenalin (1 microM) caused a 76% inhibition (P < 0.01). 4. Islets from 3-MC pretreated animals displayed similar responsiveness to all agents tested except arachidonic acid, carbachol and forskolin. Insulin release in response to arachidonic acid and carbachol was enhanced 5.2 and 5.0 fold, respectively, by 3-MC pretreatment (P < 0.001 compared to control islets incubated with 3 mM glucose); the effect of forskolin on insulin output was significantly decreased (20%; P < 0.01) compared to control islets. 5. 3-MC pretreatment did not cause any significant differences in food intake, plasma glucose or total islet insulin content. Incubation of islets with 3-MC in vitro (1 microM - 10 mM) did not affect basal or glucose-stimulated insulin release. 6. These data suggest that CYP1A-like protein expression within the pancreatic islets of Langerhans is inducible and may have a role in the alteration of pancreatic beta-cell secretory responsiveness.
Clarke
J
J
School of Biomedical Sciences, University of Ulster, Coleraine, Co. Londonderry, N. Ireland.
Flatt
P R
PR
Barnett
C R
CR
D000818:Animals; D016718:Arachidonic Acid / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis / Q000502:physiology*; D004790:Enzyme Induction / Q000187:drug effects; D007150:Immunohistochemistry; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000201:enzymology* / Q000378:metabolism; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D007328:Insulin; D016718:Arachidonic Acid; D008748:Methylcholanthrene; D003577:Cytochrome P-450 Enzyme System; D013755:Tetradecanoylphorbol Acetate