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(The FASEB Journal. 1998;12:1581-1587.)
© 1998 FASEB

RESEARCH COMMUNICATION

Aromatic hydroxylation in animal models of diabetes mellitus

Barbara Lubeca, Michael Hermona, Harald Hoegerb, and Gert Lubecc,1

a Department of Neonatology and Intensive Care, University of Vienna, A 1090 Vienna, Austria
b Institute of Animal Breeding, University of Vienna, A 1090 Vienna, Austria
c Department of Pediatrics*, University of Vienna, A 1090 Vienna, Austria


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Although the involvement of oxidative stress is well documented in the diabetic state, the individual active oxygen species generated have not been demonstrated in animal models of diabetes currently used. Since streptozotocin-induced diabetes mellitus in animals still serves as an animal model of diabetes mellitus, but streptozotocin induces diabetes and generates oxidative stress per se, we decided to study whether aromatic hydroxylation reflecting hydroxyl radical attack was found in three animal models of diabetes mellitus without streptozotocin induction or in streptozotocin-induced diabetes only. For this purpose, we compared lipid peroxidation, aromatic hydroxylation of phenylalanine, glycoxidation in genetically determined diabetic mouse strains db/db and kk, and the diabetic BB rat to these parameters in the streptozotocin-treated rat. Kidney malondialdehyde concentrations, reflecting lipid peroxidation, pentosidine, and N{epsilon}-caboxymethyllysine concentrations, reflecting glycoxidation, were significantly elevated in all diabetic groups as compared to their nondiabetic mates. Aromatic hydroxylation was significantly elevated in the streptozotocin-induced diabetic state exclusively. We conclude that biochemical, pathophysiological, and treatment studies in the streptozotocin model of diabetes mellitus may be confounded by the presence of products, reactions, and tissue damage generated by aromatic hydroxylation reflecting hydroxyl radical attack. We suggest it is not the diabetic state but streptozotocin that generates the hydroxyl radical, as reflected by aromatic hydroxylation in this model.—Lubec, B., Hermon, M., Hoeger, H., Lubec, G. Aromatic hydroxylation in animal models of diabetes mellitus. FASEB J. 12, 1581–1587 (1998)


Key Words: hydroxyl radical • streptozotocin • db/db mouse • BB rat • KK mouse • o-tyrosine • glycoxidation • pentosidine • carboxymethyllysine • malondialdehyde • lipid peroxidation


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
OXIDATIVE GLYCATION AND FREE radical production were clearly reviewed by Hunt and Wolff (1): glucose may oxidize under physiological and diabetic conditions leading to the production of protein reactive ketoaldehydes, hydrogen peroxide, and other highly active oxygen species (AOS).2 Glucose is also able to modify proteins by the attachment of its oxidation-derived aldehydes, leading to the development of novel protein fluorophores as well as fragment protein via free radical mechanisms. Fragmentation of proteins by glucose is inhibitable by metal chelators, free radical scavengers such as benzoic acid and sorbitol, and the antioxidant enzyme catalase. Protein glycation and oxidation are inextricably linked. Halliwell and Gutteridge (2) illustrated a possible mechanism for the production of the hydroxyl radical (·OH) from autooxidation of monosaccharides: after an enolization reaction of the sugar, the enediol anion is oxidized by a metal catalyzed reaction, forming an enediol radical that, in turn, is oxidized in the presence of oxygen and metal catalysis to the corresponding dicarbonyl and generation of hydrogen peroxide and the ·OH.

Further support for the production of biologically relevant AOS by autooxidative glycation came from Carubelli and co-workers (3). They incubated the RNA phage Q beta with a mixture of ribose and a copper salt, which resulted in a complete loss of viability. There was a direct correlation between the decrease in phage survival and incubation time, ribose, and copper concentration. Addition of the chelator diethylenetriaminepentaacetic acid abolished the toxic effect. These results were consistent with an initial production of superoxide free radicals by transition metal-catalyzed oxidation of ribose and Amadori products, followed by dismutation of superoxide to hydrogen peroxide and generation of the ·OH by the Fenton reaction.

Hiramoto and co-workers (4) confirmed DNA breaking activity in the Maillard reaction of glucose–amino acid mixtures. Maillard products of heated glucose–amino acid mixtures induced single-strand breaks of DNA after incubation at physiological conditions. Products of glycine, histidine, tryptophan, phenylalanine, and cysteine transformed a plasmid supercoiled DNA into an open, circular relaxed, and a linear form. DNA breaks were not abolished by scavengers of ·OH or singlet oxygen.

Although well supported biochemically, information on the involvement of AOS in animal models of diabetes mellitus (DM) is poor.

Ohkuwa and co-workers (5) showed ·OH formation in diabetic rats induced by streptozotocin (STZ). They showed ·OH generation using aromatic hydroxylation of salicylic acid correlating with the STZ dose. They do not rule out, however, that STZ may be a generator of oxidative stress itself, and therefore the differentiation between diabetes-related ·OH generation and STZ-related ·OH production is impossible and cannot answer the question of whether the ·OH is generated by the diabetic state per se.

We therefore decided to evaluate aromatic hydroxylation reflecting ·OH attack, lipid peroxidation (LPO), pentosidine (P), and N{epsilon}-carboxymethyllysine (CML) as markers of glycoxidation in an animal model with STZ-induced DM and three genetically mediated animal models of DM.

Aromatic hydroxylation was found in the STZ-induced animal model of DM only, suggesting that not the diabetic state, but STZ, can be incriminated for increased aromatic hydroxylation (i.e., generation of the ·OH).


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Animals
kk mice
Spontaneously diabetic kk mice supplied by Prof. Dr. L. Herberg (Deutsches Diabetesforschungsinstitut, Duesseldorf, Germany) were bred and kept at the Institute of Versuchstierzucht, Himberg, Austria. The kk mouse is used as a model of noninsulin-dependent DM, and the renal lesions that occur closely resemble the human diabetic nephropathy. The strain is characterized by slowly developing obesity, mild hyperglycemia, and hyperinsulinism. For the severity and progression of diabetic disease, calorie intake is all-important. Metabolic abnormalities are maximal at an age of 5 months and normalize at an age of 12 months. Hyperglycemia is mainly due to hyperinsulinism. The life span of the diabetic kk mouse is shorter than their nondiabetic siblings (ddy, nondiabetic mice with kk genetic background), which were used as control group in this study (6).

As all other experimental animals used in this study, 10 female diabetic and 10 female nondiabetic mice were kept under a day/night rhythm at 23°C and had free access to tap water and mouse cake (Altromin). Drinking volume and food intake were measured and did not differ significantly in the animal systems of noninsulin-dependent DM (kk and db/db).

Body weight for controls at the start of the experiments (8 months of age) was 21.8 ± 3.8 g, and at the end (12 months of age) was 37.2 g ± 2.4 g; for diabetic animals, body weight was 29.0 ± 4.0 g at the start and 62.5 ± 13.6 g at the end of the protocol.

db/db mice
Db/db mice and their nondiabetic siblings, the C57BL/Ks strain, were purchased from Shaw`s farm (U.K.) and kept during the experiments at the Institut of Versuchstierzucht.

The mutation db is a unit autosomal recessive gene with full penetrance, and causes metabolic disturbances in homozygous mice resembling noninsulin-dependent DM in humans. Abnormal deposition of fat at 3–4 wk of age is followed by hyperglycemia, polyuria, and glycosuria. The diabetic condition appears to develop in two stages. In the early stage there are marked increases in the levels of plasma insulin, the rates of lipogenesis and gluconeogenesis, and low glucose oxidation; there is a reduction of ß-cell granules in the islets of Langerhans, with other changes suggestive of a compensating adaptation to increased insulin demand. The late stage is characterized by a nearly normal level of circulating insulin and a marked decrease in glucose utilization, but with a continued high rate of gluconeogenesis. These findings suggest a defect in the peripheral utilization of insulin rather than in the synthesis and release of the hormone from the pancreas (7).

Ten female diabetic db/db mice and 10 matched controls were used. Their body weight at the start of the experiments (3 months of age) was 20.8 ± 3.1 g and at the end (7 months of age) was 28.2 g ± 2.7 g in the controls; for diabetic animals, body weight at the start was 43.0 ± 4.8 g and at the end of the protocol body weight was 68.5 ± 6.6 g.

BB rats
The spontaneously diabetic BB rat is an animal model of human insulin-dependent DM (8). The disease is believed to result from the selective autoimmune destruction of ß-cells by cell-mediated and/or humoral responses (9, 10). Both sexes are affected, with the incidence of DM beginning around the age of sexual maturation and reaching a peak at 80–100 days. The DM syndrome is characterized by many features of autoimmunity, including intense infiltration of islets by mononuclear cells (insulitis) and the presence of circulating antibodies against islet cells.

Ten diabetic female BB rats and 10 of their nondiabetic siblings were purchased from (Centre de Selection et dÉlevage dÁnimaux de Labaratoire C.N.R.S., Orleans, France) and housed at the Institute of Animal Breeding, Himberg, Austria. Rats with DM were treated with insulin, as recommended and described (11). The age at start of the study was 3 months; the body weight in BB with DM was 165 ± 16 g in contrast to nondiabetic BB rats, with a body weight of 153 ± 20 g.

At the end of the study period (7 months), the body weight was significantly lower in BB with DM (286±12 g, P<0.01) than in nondiabetic controls (316±14 g). Drinking water but not food uptake was significantly increased as well (P<0.01, data not shown).

STZ-induced DM in the rat
Streptozotocin is a nitrosurea compound used for more than a decade to induce DM in experimental animals (12, 13). It produces DNA strand breaks in islet cells; several mechanisms, including alkylation of DNA, have been proposed to kill the ß-cell (2, 14). Injection of STZ has also been shown to decrease CuZnSOD activity of islet cells; vitamin E has been reported to decrease the diabetogenicity of STZ in rats; and injected SOD has been claimed by some groups to decrease STZ diabetogenicity, though not unequivocally (15–20). Although the exact mechanisms leading to the induction of DM are not fully elucidated, STZ-induced DM is used in many animal studies of DM, perhaps for financial reasons (genetic models are much more expensive), simplicity of handling, and the rapidity of occurrence of `diabetic' complications.

Ten female Sprague/Dawley rats (4 months old, 250–289 g body weight) (Institut of Versuchstierzucht) were injected via the tail vein with STZ (Sigma) [50 mg/kg body weight in 0.1 M citrate buffer, pH 4.5]; the development of DM was checked by ketostix (Ames Laboratories) and verified by blood glucose determinations (Haemostix, Boehringer-Mannheim, Mannheim, Germany). Ten matched animals, serving as controls, received injections of isotonic sodium chloride. At the end of the study, when animals were 7 months of age, those treated by STZ showed a body weight of 286 ± 16g; untreated controls weighed 389 ± 17 g.

Glycemic control
To determine blood glucose at the end of the experiments, a standard glucose oxidase assay was used. Fructosamine levels were determined using a commercially available fructosamine kit (Fructosamin kit, Hoffmann-La Roche, Basel, Switzerland).

Determination of malondialdehyde (MDA)
The method of Draper and co-workers was used (see ref 21) to determine the amount of malondialdehyde in kidney samples. Kidney tissue (40–50 mg) was added to 1 ml 10% trichloroacetic acid (TCA) and 50 µl butylhydroxytoluol (2 mg/ml methanol), heated for 30 min under constant shaking to 95°C, and spun down at 5000 x g. TCA extract (150 µl) plus 150 µl thiobarbituric acid reagent (60 mg/10 ml H2O) were heated for 30 min at 95°C. After cooling, the mixture was extracted with 0.6 ml of n-butanol and the extract was centrifuged. For high-performance liquid chromatography (HPLC) analysis, 0.3 ml of the supernatant was added to 0.6 ml of the eluant.

The procedure of Wong and co-workers was followed (22) for HPLC. A Lichrospher RP18 column, 125 x 4 mm, was used; the eluant was 50 mM phosphate buffer, pH 6.8:MeOH=60:40, flow l ml/min, and detection was carried out with a Jasco fluorescence detector Mod FP 920 at the excitation of 525 nm and emission of 550 nm. Quantification was standardized externally by tetraaethoxypropane (0.1–0.5 nmol in 50 µl H2O).

Determination of pentosidine (P)
Kidney tissue P was determined after sample preparation by Takahashi and co-workers (23) and run according to the method published by Sell and co-workers (24). A Shimatsu pump LC6A was used; the sampler was an SIL and SCL-6B (Shimadzu), the integrator a CR4AX, and the detector a Jasco fluorometer 820 FP.

Determination of N{epsilon}-carboxymethyllysine
Aliquots (30 mg) of kidney tissue were rinsed with distilled water and hydrolyzed by 6N HCl for 12 h [or 6 h for o-tyrosin (OT)] at 105°C under nitrogen. The hydrolyzate was centrifuged at 4000 x g for 10 min and ion exchanged, as described earlier (25). HPLC analysis was carried out by reversed phase HPLC after precolumn derivatization using o-phthalaldehyde and 3-mercaptopropionic acid. Instruments used included a Merck-Hitachi 655a-12 liquid chromatograph, F 1000 fluorescence spectrophotometer, an L 5000 LC controller, and a D 2000 chromointegrator.

Derivatization was with o-phthalaldehyde and borate buffer (pH 10.4) according to a published standard protocol (26). The column was a Hypersil ODS (3 µm; Shandon), 125 x 4 mm; the guard column was an RP18 (7 µm, 15x3.2 mm) placed between the pumping system and analytical column. Filters of 2 µm, 1.6 mm ID frit (HP 01.0–27602) were placed between injector and analytical column.

The mobile phase (eluant A) was 25 mM NaOAc (pH 7.2) with 0.7% THF; eluant B: 100 mM NaOAc, pH 7.2, in acetonitrile (1:4 v/v). The gradient run was exactly as detailed previously (27).

Determination of o-tyrosine
OT and phenylalanine were determined in the 6 h hydrolyzates mentioned above by reversed phase HPLC; separation was run on a Supersphere 100, 4 µm, 100 x 4.6 mm column, using fluorescence detection as reported by Ishimitsu et al. (28). The pump used was a Shimadzu LC6A, the sampler was an SIL and SCL-6B (Shimadzu), and the integrator was a CR4AX. A Jasco fluorometer 820 FP detector was used to measure emission absorbance at 305 nm after excitation at 275 nm.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Means and SD of kidney MDA, P, CML, OT, plasma glucose, and fructosamine are shown in Table 1 and Fig. 1. MDA, CML, P, glucose, and fructosamine were significantly higher in diabetic animals than in their nondiabetic controls. OT, however, was significantly higher in STZ-induced diabetic animals only.


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  		Table 1. Means and SD of kidney MDA, CML, pentosidine, OT, plasma glucose, and plasma fructosamine in diabetic (D) and control (C) animals



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  		Figure 1. Distribution of kidney MDA,CML, pentosidine, and OT in diabetic (D) and control (C) animals. An asterisk reveals the major finding of significantly increased OT in STZ-treated rats exclusively.

Linear regression analysis showed a significant correlation between glucose and fructosamine in db/db mice (r=0.77), glucose and P in db/db mice (r=0.82; Fig. 2A), glucose and CML in db/db mice (r=0.75; Fig. 2B), and P and CML in db/db mice (r=0.69; Fig. 2C); a significant association was also found between CML and OT in STZ-induced diabetic rats (r=0.68; Fig. 2D).






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  		Figure 2. A strong association was found between plasma glucose and pentosidine (A), glucose and CML (B), CML and pentosidine (C), and CML and OT (D).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
As shown in Results, kidney MDA levels were consistently higher in the four diabetic animal models of DM than in their nondiabetic counterparts. This confirms earlier work on lipid peroxidation in animal models and in human disease (29–37).

However, we provide information that increased tissue MDA is increased not only in the STZ-induced diabetic animals, which would be expected by the administration of the oxidative stress generator STZ per se, but also in three genetic models of DM. A first approach to test MDA in kidneys of a genetic mouse model was the thiobarbituric acid test performed by Yaguchi and co-workers (33). They showed increased MDA in diabetic kidney samples, but the test system they used (34) could have been measuring aldehydes from nonenzymatic glycation and not those derived from lipid peroxidation. We also confirm findings of increased lipid peroxidation in diabetic BB rats as evaluated by increased expired pentane by Pitkanen and co-workers (30).

Increased tissue MDA as a reactive aldehyde may well be involved in the development of diabetic complications such as aldehydes derived from nonenzymatic glycation or glucose metabolism in DM.

The glycoxidation parameter P (4, 38–45), in turn, was significantly elevated in kidneys of all four diabetic models as compared to their nondiabetic mates. Furthermore, in the diabetic db/db mouse, we revealed a strong association between the two glycoxidation parameters P and CML and a strong correlation with glucose, a link already found in vivo by others (44, 45). Glycoxidation is a hallmark of the diabetic state (46), but failed to correlate with lipid peroxidation parameter MDA and ·OH parameter OT. We are confirming increased glycoxidation in DM by our findings in diabetic animals that developed independently of LPO or the ·OH in terms of aromatic hydroxylation.

The glycoxidation parameter CML (38, 47, 48) was increased in all diabetic models we studied. In the case of STZ-induced DM, a significant link between CML and the aromatic hydroxylation parameter OT was found, suggesting the involvement of the ·OH in the formation of CML and/or DM by STZ induction. It was, however, reported that lipid peroxidation per se can lead to CML formation, which means that the generation of CML does not depend on the presence of the ·OH (48); there was no association between MDA and any glycoxidation parameter in any animal model of DM in our study.

The most prominent finding was the increased kidney OT found in the STZ-induced diabetic rats exclusively. None of the other genetically determined animal models of DM showed increased OT, indicating that STZ rather than DM could be incriminated for the generation of OT. This observation is in line with an earlier study in db/db mice showing that heart OT was comparable to nondiabetic controls (49).

OT is a reliable parameter for aromatic hydroxylation, reflecting protein oxidation (46, 50–53) and ·OH attack (54). It has been described as being generated in a series of oxidative conditions from ozone exposure (55), hyperoxia (56), administration of hydrogen peroxide (21), and irradiation (57). OT generation parallels ·OH attack, as recently shown by Krajnik and co-workers (58). As no correlation with glycemic control (i.e., fructosamine or glucose) was found, no support for the generation of OT by glucose autooxidation itself can be provided. The strong association with the glycoxidation parameter CML in the STZ-induced model may indicate CML generation by the ·OH generator STZ in addition to the oxidative mechanisms of glycoxidation.

Our findings agree with Ohkuwa and co-workers (5), who showed that ·OH generation was reflected by aromatic hydroxylation in STZ-induced DM. They used the principle of salicylate hydroxylation by the ·OH, which is another technique to show ·OH attack by aromatic hydroxylation (5). Because salicylate per se can influence oxidant status, we preferred to test hydroxylation of an endogenous aromatic compound (phenylalanine) in order to avoid exogenous (salicylate) confounding factors.

We suggest that the aromatic hydroxylation found in the STZ-induced model of DM exclusively may not be caused by the diabetic state, but rather by STZ per se. We therefore conclude that biochemical, pathophysiological, and treatment studies in the STZ model of DM may be confounded by the presence of products, reactions, and tissue damage generated by aromatic hydroxylation, reflecting hydroxyl radical attack.


   ACKNOWLEDGMENTS
 
We are highly indebted to the Red Bull Corp., Salzburg, Austria, for generous financial support.


   FOOTNOTES
 
1 Correspondence: University of Vienna, Department of Pediatrics, Waehringer Guertel l8, A l090 Vienna, Austria. E-mail: gert.lubec{at}akh-wien.ac.at

2 Abbreviations: DM, diabetes mellitus; HPLC, high-performance liquid chromatography; ·OH, hydroxyl radical; AOS, active oxygen species; STZ, streptozotocin; LPO, lipid peroxidation; P, pentosidine; CML, N{epsilon}-carboxymethyllysine; MDA, malondialdehyde; OT, o-tyrosin; TCA, trichloroacetic acid.

Received for publication March 11, 1998.
   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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