Reappraisal of xenobiotic-induced, oxidative stress-mediated cellular injury in chronic pancreatitis: A systematic review

Table 1 Evidence for cytochrome induction in pancreatic acinar cells in chronic pancreatitis

Ref.	Cytochrome	Method of assessment	Histologic verification	Increased expression in acinar cell	Functional correlate
Foster et al[20]	CYP 3A1	Immunohistochemical staining > 50% of healthy donor	No	CYP 3A1	No
	CYP 2E			CYP1A2
	CYP1A2			NADPH 4501
	NADPH 4501
	Glutathione
Wacke et al[21]	CYP1A1	No of cases having high ratios compared to control	Yes	CYP1A12	Yes (verapamil biotransformation)
	CYP1A2			CYP1A2
	CYP2C9			CYP2E1
	CYP2E1			CYP 3A12
	CYP3A1
Standop et al[22]	CYP1A1, 2	Differences in frequency of immunopositivity between normal, CP and cancer	Yes	CYP1A	No
	2B6			CYP 2B6
	2C 8/9/19			CYP 2C8/9/19
	2D6			2D6
	2.00E + 01			NA-OR
	3A4
	NA-OR

¹NADPH cytochrome P 450 reductase;

²Expression similarly increased in normal non-diseased controls. CYP: Cytochrome P450; NA-OR: NADPH oxio reductase.

Table 2 Interventions with evidence of modulation of experimental chronic pancreatitis

First Author	Animal	Model of CP	Intervention	Modes of action	Time course and point of intervention	Pancreatic parenchymal end-points	Systemic end-points
Gómez et al[43]	Rat	ip cyclosporine A and ip caerulein	Vitamin E (gavage)	Anti-oxidant properties: control oxidative radicals	15 d study	Reduced peroxidation (TBARS level)	Reduced plasma lipoperoxidation. Reduced plasma TGF-β
				Anti-oxidant independent properties: reduction of fibrosis	Intervention day 8	Reduced collagen and hyaluronic acid deposition
						Reduced acinar atrophy and periductal fibrosis
Yoo et al[44]	Mouse	ip caerulein	DA 9601	Phytochemical possessing anti-inflammatory and antioxidative action	35 d	Reduced pancreatic fibrosis	None
					Intervention weekly from week 1	Myeloperoxidase and iNOS activities decreased
						HSP-70 increased
de Las Heras-Castaño et al[45]	Rat	ip cyclosporin A and ip caerulein	L-methionine β-carotene ascorbic acid α-tocopherol selenium	Antioxidant	49 d	Reduction in pancreatic fibrosis	None
					Intervention weekly from week 1	Similar cellular glutathione peroxidase levels to control and less than caerulein alone group
						Increased total antioxidant status but also increased in caerulein alone group
Mas et al[46]	Rat	Intraductal TNBS	Taurine	Anti-fibrotic	28 d	Tissue malondialdehyde levels increased	Reduction in weight loss
					Intervention weekly from week 1	SOD and glutathione peroxidase activities decreased
						Histopathologic injury scores lower
Lu et al[47]	Rat	DBTC infusion1	Ascorbic acid	Antioxidant	56 d	Increased SOD and reduce malondialdehyde	Reduce serum hyaluronic acid
					Intervention weekly from day 28	No change in pancreatic fibrosis
						Less atrophy
Wei et al[48]	Rat	PD infusion of pancreatic juice/bile (PD hypertension)	Pravastatin 10 mg/kg per day	Competitive inhibition of 3-hydroxy-3-methylglutarylcoenzyme A reductase	14 d	Maintained secretin-stimulated secretory response	Amelioration of weight loss
					Intervention from day 2	Attenuated fibrosis with less expression of TGF-β mRNA
						Maintained pancreatic exocrine function
Li et al[49]	Rat	Intraductal TNBS	α-tocopherol	Antifibrotic	28 d	Reduced incidence of pseudocysts from 100% to 69%	Amelioration of weight loss
					Intervention daily	Ameliorates pancreatic fibrosis
Jiang et al[50]	Rat	DBTC	α-tocopherol and tocotrienol-rich fraction	Antioxidant and antifibrotic	28 d	Reduced pancreatic inflammation and fibrosis	None
					Intervention daily (oral)	Down-regulated mRNA expression of TGF-β1 and collagen-α1
Matsushita et al[51]	Rat	DBTC	Taurine	Antifibrotic	28 d	Inhibition of pancreatic fibrosis	None
					Intervention day 0	Decreased apoptotic index

¹Dibutylin dichloride (DBTC) given by infusion into tail vein. TBARS: Thiobarbituric acid-reactive substance; TGF-β: Transforming growth factor beta; iNOS: Inducible nitric oxide synthase; HSP: Heat shock protein; TNBS: Trinitrobenzene sulfonic acid; SOD: Superoxide dismutase; PD: Pancreatic duct.