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Artificial casein micelles were prepared by adding 30 mM calcium, 22 mM phosphate and 10 mM citrate to sodium caseinate solutions, and the content of the casein aggregates cross-linked by colloidal calcium phosphate was determined by high-performance gel chromatography on a TSK-GEL G4000SW column in the presence of 6 M urea. The content of the casein aggregates cross-linked by colloidal calcium phosphate in artificial whole casein micelles was 48% of total casein, and their relative casein composition determined by high-performance ion-exchange chromatography was 53.1% for alpha s1-casein, 15.8% for alpha s2-casein, 31.1% for beta-casein and 0% for kappa-casein. The order of cross-linking by colloidal calcium phosphate agreed with that of the ester phosphate content of casein constituents. The content of the casein aggregates cross-linked by colloidal calcium phosphate was higher in alpha s1-kappa-casein micelles than in beta-kappa-casein micelles. kappa- and gamma-caseins and dephosphorylated alpha s1-casein were not cross-linked by colloidal calcium phosphate. Although kappa-casein was not cross-linked, chemically phosphorylated kappa-casein, of which the average phosphate content was 8.5 per molecule, was cross-linked. It is concluded that caseins are cross-linked through their ester phosphate groups by colloidal calcium phosphate.
Two types of casein hydrolysates, casein A (mean peptide length 3.3) and casein B (mean peptide length 17.4) were prepared by the enzymatic hydrolysis of casein, and their effects on in vitro dissolution rates and oral bioavailability of drugs were evaluated. The in vitro dissolution behavior of the kneaded mixture of three drugs (diclofenac acid, diazepam, and prednisolone) with caseins A and B were significantly improved compared to the drugs alone, even at 1:1 weight ratio of drug and casein hydrolysate, even though casein A and casein B did not interact with drug molecules in the kneaded mixture. Only diclofenac, an acidic drug, showed an increased dissolution rate with added casein hydrolysates, and a more rapid dissolution with casein A than with casein B was observed. When the dissolution of prednisolone from kneaded mixture was compared at pH 1.2 and 6.8, the dissolution rate of prednisolone from the casein A kneaded mixture was considerably higher than that of prednisolone powder at both pHs, and the rate from the casein B kneaded mixture was higher only at pH 6.8. The plasma concentration-time profile showed that prednisolone was completely and rapidly absorbed from the casein A kneaded mixture as well as the prednisolone solution. In addition, prednisolone in the kneaded mixture with casein B was more difficult to absorb up to 1 hr after administration in comparison to prednisolone powder. The slow and lowered absorption of prednisolone by casein B might be explained by conversion of casein B to a shorter soluble peptide in the gastrointestinal tract and by the slow dissolution of prednisolone at acidic conditions. The toxicological tests revealed that casein hydrolysate is a safe drug carrier. Consequently, casein hydrolysates might be safely used to control the dissolution rate and bioavailability of a variety of drugs, depending on the peptide length of the casein fragments.
The effect of the ripening time on the proteolytic process in cheeses made from ewe's milk during a 139-day ripening period was monitored by the use of capillary electrophoresis of pH 4.6 insoluble fraction. Totals of 18 and 21 peaks were recognized and matched in the electropherograms obtained with a fused-silica capillary and a neutral capillary (hydrophilically coated), respectively. These peaks correspond to intact ovine caseins and their hydrolysis products (alpha(s1)-casein I, alpha(s1)-casein II, alpha(s1)-casein III, alpha(s2)-casein, beta(1)-casein, beta(2)-casein, p-kappa-casein, alpha(s1)-I-casein, gamma(1)-casein, gamma(2)-casein, and gamma(3)-casein). The alpha(s)-caseins (alpha(s1)- and alpha(s2)-casein) displayed similar degradation pattern to one another, but different from those of beta-caseins (beta(1)- and beta(2)-casein). beta-Caseins were very much undergoing lesser degradation during the ripening time than alpha(s)-casein. Finally, partial least-squares regression and principal components regression were used to predict the ripening time in cheeses. The models obtained yielded good results since the root-mean-square error in prediction by cross validation was <8.6 days in all cases.
In order to investigate the role of food antigen-specific T cells circulating in the blood of patients with food allergy, we compared T cell response to three casein components (alpha s-, beta- and, kappa-casein) with specificities of IgG and IgE binding to the casein components in four milk-allergic patients (P1-4) with atopic dermatitis. In all patients the binding activities of IgG antibodies to alpha s-casein were most dominant, followed by those to beta- and to kappa-casein. The major component of casein bound by IgE antibodies was alpha s-casein in P1 and P3, kappa-casein in P2, and alpha s-casein as well as kappa-casein in P4; the order of casein components bound by IgE antibodies was different from that by IgG antibodies. Proliferative responses of peripheral blood mononuclear cells (PBMC) to casein components were so low that the dominance of casein recognition could not be clearly demonstrated. However, short-term T cell lines that specifically respond to casein were successfully established from PBMC of the four patients and the proliferative responses of the T cell lines to the three components of casein were in accord with the IgE antibody specificity to casein components but not with that of IgG antibody specificity. When taken together, these results indicate that casein-specific T cells circulating in the blood are involved in or reflect an allergic reaction against casein.
To determine bioavailability, expressed as the protein efficiency ratio (PER) and biological value (BV) in rats, of the epsilon-(gamma-glutamyl)lysine [epsilon-(gamma-Glu)Lys] moiety in crosslinked proteins, we prepared heavily crosslinked [21.5 /micromol epsilon-(gamma-Glu)Lys/g casein] and intermediately crosslinked [13.6 micromol epsilon-(gamma-Glu)Lys/g casein] casein, using microbial transglutaminase. In Experiment 1, rats were assigned to one of four diets (heavily or intermediately crosslinked caseins, intact casein or non-protein diet) for 4 wk to evaluate the bioavailability of the epsilon-(gamma-Glu)Lys moiety in crosslinked casein as the sole source of dietary protein. Rats that were fed intact casein and the two crosslinked caseins had similar growth rates, PER, and BV, indicating that crosslinked caseins supported the growth of rats similarly to the intact casein. In Experiment 2, heavily crosslinked casein was added to wheat gluten-based diets in concentrations of 20 and 40 g/kg diet to evaluate the bioavailability of lysine in the epsilon-(gamma-Glu)Lys moiety of the casein as a lysine supplement for lysine-poor gluten. One of six diets (heavily crosslinked or intact casein diets in the two concentrations, gluten diet, or non-protein diet) was fed to rats for 4 wk. No significant differences in food intake, body weight gain, PER or BV were observed among rats fed the intact or crosslinked casein diets at either 2 or 4 g/100 g casein. These results suggest that the epsilon-(gamma-Glu)Lys moiety in crosslinked caseins are absorbed and therefore supplement the gluten. HPLC analysis of urine and feces of rats fed the crosslinked caseins actually confirmed that approximately 99% of the epsilon-(gamma-Glu)Lys moiety was absorbed in the body.
To improve acid clotting properties, enzymic dephosphorylation of caseins with calf intestinal alkaline phosphatase (CAP) or potato acid phosphatase (PAP) was investigated. Greater dephosphorylation was achieved using alpha s1- or beta-casein as substrates, compared to whole casein or skim milk. Electrophoresis of PAP-modified caseins revealed bands with lower mobility and a multibanded pattern in the beta-casein region which was similar to that of human beta-casein. On the other hand, CAP modification produced electrophoretic bands having lower mobility of the beta-casein component, but with higher mobility in the alpha s1-casein component as well as increased net negative charge in the CAP-casein. PAP-casein formed a fine dispersion upon acidification to pH 4, with a microstructure similar to that of acidified human casein. Greater initial rates of hydrolysis by pepsin at pH 4 were observed for both CAP- and PAP-modified caseins, compared to bovine and human caseins. The rate and extent of hydrolysis remained high for CAP-casein but tended to level off with PAP-casein during sequential digestion with pepsin and pancreatin. There may be advantages in the use of partial dephosphorylation to improve acid clotting and digestibility properties of bovine casein for infant feeding.
1. Explants of mammary gland from mid-pregnant rabbits were cultured in medium 199 containing insulin, prolactin and cortisol, and specific anti-casein immunoglobulin G was used to measure the amount, rate of synthesis and rate of degradation of casein in the explants in the presence of hormones and after removal of hormones from previously stimulated tissue. 2. The amount of casein in particle-free supernatants prepared from mammary explants was measured by ;rocket' immunoelectrophoresis. 3. The rate of incorporation of l-[4,5-(3)H]leucine into casein was measured after isolation of the casein by immunoadsorbent chromatography and polyacrylamide-gel electrophoresis in the presence of urea and sodium dodecyl sulphate. 4. Casein accumulates in mammary explants in the presence of insulin, prolactin and cortisol, but not in the absence of hormones. Removal of hormones after 24h in culture results in a decrease in the rate of accumulation of casein in the explants. 5. Casein-synthetic rate increases in mammary explants in the presence of insulin, prolactin and cortisol, but not in the absence of hormones. Removal of hormones after 24h in culture results in continued casein synthesis at approx. 30% of the rate in the presence of hormones. The synthetic rate does not decrease to values observed in explants cultured throughout in the absence of hormones. 6. Casein is not degraded in mammary explants during a phase of rapid casein accumulation (36-72h) in the presence of hormones. Furthermore casein is not degraded when hormones are removed from the tissue after between 36 and 72h in culture. 7. Casein is glycosylated in mammary explants; the extent of glycosylation parallels the rate of synthesis. The glycosylated protein is rapidly secreted from the tissue. 8. The results are consistent with the notion that after hormonal stimulation mammary explants from mid-pregnant rabbits synthesize, glycosylate and rapidly secrete casein. Removal of hormones decreases the synthetic rate of casein, but does not cause the accumulation of a pool of degradable casein in the lobuloalveolar cells.
To develop a molecular basis for structure-function relationships of the complex milk protein system, an energy-minimized, three-dimensional model of a casein submicelle was constructed consisting of kappa-casein, four alpha s1-casein, and four beta-casein molecules. The models for the individual caseins were from previously reported energy-minimized, three-dimensional structures. Docking of one kappa-casein and four alpha s1-casein molecules produced a framework structure through the interaction of two hydrophobic antiparallel sheets of kappa-casein with two small hydrophobic antiparallel sheets (residue 163-174) of two preformed alpha s1-casein dimers. The resulting structure is approximately spherically symmetric, with a loose packing density; its external portion is composed of the hydrophilic domains of the four alpha s1-caseins, while the central portion contains two hydrophbic cavities on either side of the kappa-casein central structure. Symmetric and asymmetric preformed dimers of beta-casein formed from the interactions of C-terminal beta-spiral regions as a hinge point could easily be docked into each of the two central cavities of the alpha-kappa framework. This yielded two plausible energy-minimized, three-dimensional structures for submicellar casein, one with two symmetric beta-casein dimers and one with two asymmetric dimers. These refined submicellar structures are in good agreement with biochemical, chemical, and solution structural information available for submicellar casein.
We have previously reported that subcutaneous injection of casein, a potent inducer of the immunomodulatory acute phases reactant, serum amyloid A (SAA) protein, produces a marked suppression of humoral responses that require macrophage accessory cell cooperativity in the B6C3F1 mouse. The objective of these studies was to further characterize the immunological changes produced by casein treatment. It was observed that the inhibition of the sRBC IgM AFC response which accompanies casein treatment is dose related to the amount of casein introduced subcutaneously to the mouse. These studies, as well as those previously reported by several laboratories including our own have demonstrated that spleen cells isolated from casein-treated mice also exhibit markedly suppressed humoral responses in vitro. However, casein added directly to naive spleen cell cultures at concentrations significantly higher than those which would be found in the lymphoid tissues of the intact animal have no direct inhibitory effect on the sRBC IgM AFC response, suggesting that casein alone does not exert a direct immunosuppressive effect. Kinetics of recovery studies indicate that the casein-induced immunosuppression is readily reversible. Humoral responses are fully recovered within 3 days, once subcutaneous injections of casein are terminated. In vitro measurements of IL-1 secretion following stimulation of splenic macrophages, isolated from casein treated mice, with lipopolysaccharide indicate no significant effect on the capacity of these cells to produce this cytokine. Direct addition of recombinant IL-1 or interferon-gamma to spleen cell cultures isolated from casein-treated mice also was found to be incapable of reversing the inhibited IgM AFC response. Taken together, these studies strongly suggest that the accessory cell dysfunction associated with macrophages from casein-treated mice is not due to the inability of these cells to secrete IL-1 and indicate that the dysfunction cannot be reversed by IL-1 or interferon-gamma. Casein treatment was also found to markedly inhibit DTH, a cell-mediated immune response requiring macrophage accessory cell function. interestingly, the DTH responses were only affected by casein when it was administered post-sensitization with antigen (sRBC) but prior to antigen challenge. When casein was administered prior to sensitization with antigen, which is analogous to the treatment schedule that was found to suppress the sRBC antibody response, no effect was observed on DTH.
We have shown by gel filtration on Sepharose 4B at low ionic strength that casein kinases S (type 1), heparin-insensitive, and TS (type 2), heparin-inhibited, of rat liver cytosol participate in two distinct multimolecular systems, Ve/Vo = 1.25 and Ve/Vo = 1.90, respectively, both less retarded than the peak of cAMP-dependent protein kinase activity (Ve/Vo = 2.04). Both casein kinase I and casein kinase II complexes are unstable in 0.5 M NaCl, giving rise by gel filtration under these conditions to the free forms of casein kinase S (Ve/Vo = 2.37, Mr 34 000) and casein kinase TS (Ve/Vo = 2.10, Mr 130 000), respectively. In contrast, the elution volume of cAMP-dependent protein kinase activity is always the same irrespective of the ionic strength of the medium. Casein kinase I, accounting for the whole casein kinase S activity of cytosol, also contains a phosphorylatable 31-kDa protein (p31) which is a substrate of casein kinase S, since its phosphorylation is insensitive to heparin, the heat-stable inhibitor and trifluoperazine, but it is prevented by beryllium. Casein kinase II, on the other hand, apparently results from the association of the whole casein kinase TS (type 2) of rat liver cytosol with a 90-kDa protein substrate (p90) which is distinct from glycogen synthase according to their different peptide mappings. The radiolabelling of p90 is inhibited by heparin, unlabeled GTP and polyglutamates, while it is dramatically and specifically enhanced by polylysine. At least three more protein bands of Mr 58 000, 52 000 and 37 000 are phosphorylated by casein kinase TS in the casein kinase II fraction: their co-elution with casein kinase TS, however, seems to be accidental and their radiolabeling in the presence of polylysine is almost negligible compared to that of p90. It is concluded that p31 and p90 may represent specific targets of casein kinase S and casein kinase TS, respectively, whose intimate association with the enzymes could be functionally significant.
The main role of kappa-casein in milk is to stabilize the formation of casein micelles. Although marsupial milk contains casein micelles, kappa-casein had not been identified in any species. In these experiments, the first marsupial kappa-casein has been prepared as enriched casein fractions and the cDNA cloned from the brushtail possum (Trichosurus vulpecula). Possum kappa-casein is a 158 amino acid peptide that shares low amino acid sequence identity (20-30%) with that of eutherian kappa-caseins. In the gut of suckling young, casein micelles clot when kappa-casein is cleaved by chymosin at a specific site. Eutherian kappa-casein sequences are classified according to the sequence of the chymosin cleavage site: Phe-Met, Phe-Ile or Phe-Leu. Possum kappa-casein appears to form a separate class, with a putative chymosin cleavage site of Phe-Ala, which is different from that found in eutherian mammals. Other features of kappa-caseins, such as the location of the N-terminal cysteine, solubility in the presence of calcium, and the O-glycosylation sites on threonine residues in the C-terminus of the molecule, are conserved in the possum sequence. The kappa-casein gene was expressed throughout lactation in the mammary gland, and although mRNA levels of kappa-, alpha- and beta-casein varied between animals there appeared to be a correlation in the expression of these genes within an individual animal. This suggests that a common transcription regulatory region may be controlling expression of all three genes in the possum.
1. In Expt 1 a study was made in goats of responses in terms of milk production, nitrogen utilization and plasma amino acids to abomasas infusions of casein (45 g/d) in goats given 2.5 kg/d of a ration containing crude protein (N x 6.25) at 109 (L1) or 146 (H1) g/kg. 2. In Expt 2 a study was made in goats of responses in terms of milk production, nitrogen utilization, plasma amino acids and growth hormone levels to abomasal infusions of casein (45 g/d) or arginine (25 g/d) in goats given 2.3 kg/d of a ration containing crude protein (N x 6.25) at 104 g/kg (L2). These observations were made also in goats given a ration containing crude protein at 136 g/kg (H2). 3. Milk production in Expt 1 was 2.75, 2.45 and 2.76 kg/d on L1+casein, H1 and H1+casein treatments respectively, the response to casein infusion being significant (P less than 0.05). Milk production in Expt 2 was 1.90, 2.04, 1.96 and 1.96 kg/d on L1, L2+casein, L2+arginine and H2 treatments respectively, and the differences were not significant. 4. Total N intake in Expt 1 was 49, 58 and 64 g/d on L1+casein, H1 and H1+casein treatments respectively. Faecal N was similar on the three treatments (14 g/d), urinary N was 15, 23 and 30 g/d and milk N was 14, 12 and 14 g/d on the respective treatments. Total N intake in Expt 2 was 33, 40, 43 and 44 g/d on L2, L2+casein, L2+arginine and H2 treatments respectively. Faecal N was similar on the four treatments (12 g/d), urinary N was 7, 10, 13 and 14 g/d and milk N was 9, 9, 8 and 8 g/d on the respective treatments. 5. The concentration of indispensable amino acids in plasma was increased by casein infusion in both experiments. It was 1279, 825 and 1133 micrometers/l on L1+casein, H1 and H1+casein treatments respectively in Expt 1, and 1081, 1582, 1055 and 1163 micrometers/l on L2, L2+casein, L2+arginine and H2 treatments respectively in Expt 2. 6. The concentration of arginine in plasma was doubled 1 h after the onset of arginine infusion in Expt 2, Growth hormone levels in plasma were not increased when arginine levels rose following arginine infusion. and did not differ between treatments. 7. The results of the two experiments showed that the stimulatory effect on milk production of intra-abomasal infusion of casein was not reproduced by increasing the dietary intake of protein or by infusing arginine. The results of the second experiment showed that abomasal infusion of arginine did not stimulate production of growth hormone and that growth hormone apparently was not implicated in the effects of casein infusion on milk production.
Ovine whole casein contains 2 multiphosphorylated beta-casein components designated as beta 1 and beta 2-caseins. The complete sequence of beta 1-casein and the partial sequence of beta 2-casein have been determined from cyanogen bromide and tryptic digests. The ovine beta 1 and beta 2-caseins have the same polypeptide chain and appear to differ only in that they contain 6 and 5 phosphates respectively. The amino acid composition of ovine beta 1-casein can be written as: Asp4, Asn4, Thr10, ThrP1, Ser9, SerP5, Glu19, Gn21, Pro34, Gly5, Ala4, Val21, Met6, Ile9, Leu22, Tyr3, Phe9, Trp1, Lys12, His5, Arg3. Compared to bovine beta-casein A2, which is made up of 209 residues, ovine beta 1-casein has a deletion of 2 residues (either Pro-179--Tyr-180 or Tyr-180--Pro-181) and 20 largely conservative amino acid substitutions. Although 20% of the substitutions involve proline residues, the proline contents of ovine beta 1 and bovine beta A2-caseins are very similar, around 16%. The average hydrophobicity, calculated according to Bigelow, is 5.51 kJ/residue, which is similar to that calculated for bovine beta-casein A2. The cluster of 4 phosphorylated serine residues and the highly charged nature of the amino terminal region observed for bovine beta-casein are conserved in the ovine beta-caseins. The substitution from Ile-12 (bovine) to Thr-12 (ovine) results in a new phosphorylation site, according to the phosphorylation code proposed for caseins. This site is only partially phosphorylated hence the occurrence of both beta 1 and beta 2-caseins in ovine milk.
Rat milk contains at least three major caseins with apparent molecular weights of 41,000 (alpha-casein), 25,000 (beta-casein), and 22,000 (gamma-casein) (estimated in 10% sodium dodecyl sulfate-polyacrylamide gels). These three caseins and alpha-lactalbumin, a major whey protein, were purified from rat milk. The purified caseins and alpha-lactalbumin were used to immunize BALB/c mice, and spleen cells from these mice were hybridized with cells of the mouse myeloma SP-2/0 cell-line. We have isolated a small library of hybridoma cell-lines secreting monoclonal antibodies specific for each of the major caseins and alpha-lactalbumin from rat milk. Antibodies were tested for immunoreactivity with each of the purified milk proteins and with total rat milk proteins separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Some heterogeneity in apparent molecular weight was observed for purified alpha-casein, gamma-casein, and alpha-lactalbumin. Monoclonal antibodies against alpha-casein, gamma-casein, and alpha-lactalbumin recognized all of the molecular weight forms of the antigen for which they were specific. Each monoclonal antibody was specific for one of the caseins or alpha-lactalbumin and did not react with the other caseins or alpha-lactalbumin, suggesting that there is limited structural homology among these proteins. All of the monoclonal antibodies against the rat caseins reacted with components of mouse milk, and the monoclonal antibodies against rat gamma-casein reacted with a component of human milk of apparent molecular weight 27,000. No interspecies reactivity was observed with the antibodies against rat alpha-lactalbumin. These monoclonal antibodies are being used to develop sensitive assays for each of these major rat milk proteins.
Polyacrylamide gel electrophoresis methods were used to phenotype caseins for 2045 cows and milk serum proteins for 3870 cows distributed in 63 Quebec dairy herds. Frequencies were: alpha s1-casein A .003, alpha s1-casein B .970, alpha s1-casein C .027; beta-casein A1 .561, beta-casein A2 .421, beta-casein A3 .011, beta-casein B .007; kappa-casein A .744, kappa-casein B .256; beta-lactoglobulin A .387, beta-lactoglobulin B .613; alpha-lactalbumin B 1.00. Overall unadjusted means for 305-day production in first lactation were: 5530 +/- 26.6 kg, 197 +/- 1.0 kg, 172 +/- 1.0 kg, 3.58 +/- .009, 3.12 +/- .009 for milk yield, fat yield, protein yield, fat percentage, and protein percentage for 1687 cows for casein systems. Similar data for 2906 cows phenotyped for milk serum proteins were: 5412 +/- 20.6 kg, 193 +/- .8 kg, 170 +/- .7 kg, 3.57 +/- .007, and 3.13 +/- 007. Least squares analysis of variance showed that herd location, month of calving, age of cow at first calving, and protein variants had significant effects on production traits. alpha s1-Casein B and beta-casein A phenotypes were associated with higher milk, fat, and protein yields than other variants in the two casein systems. Milk from kappa-casein BB and beta-lactoglobulin AA phenotypes contained .13 and .05% more protein than the AA and BB phenotypes with the AB phenotype intermediate.
This study examined the chemical modification of casein with three monosaccharides [e.g., glucose (Glc), fructose (fru), and ribose (Rib)], following prolonged gentle heating to product the Maillard reaction (MR). Changes in chemical modification of casein in different sugar-casein MR was monitored using temporal patters of change in fluorescence development, UV absorbance and casein molecular mass, which was studied using SDS-PAGE and MALDI-TOF mass spectrometry. Rib-casein MRP exhibited significantly (p<0.05) advanced fluorescence development at three days, compared to Glc- and Fru-casein MRPs, which corresponded to marked (p<0.05) differences in greater UV absorption of Rib-casein MRPs later on after 15 days of processing. These results were associated with the generation of different high molecular weight complexes generated from the Rib-casein MR, compared to Glu- and Fru-casein MRPs, respectively. Antioxidant activity of all three sugar-modified caseins was also assessed when cultured with Caco-2 cells. A significant, but similar protective effect against 2,2'-azobis-(2-amidinopropane)dihydrochloride (AAPH) radical-induced cytotoxicity, and ferrous- and cupric-induced toxicity of Caco-2 cells was observed for all three sugar-casein MRPs. However, these protective effects were not significantly different among the sugar-modified caseins and native casein. The results suggest that protection of Caco-2 cells from free radical-ferrous- and cupric-induced cytotoxicity by casein was not altered by modification by MR, regardless of source of monosaccharide involved in the reaction.
Casein is a major protein in cow's milk that occurs in several variant forms, two of which are beta-casein A1 and beta-casein A2. The levels of these two proteins vary considerably in milk dependent on the breed of cow, and epidemiology studies suggest that there is a relationship between their consumption and the degree of atherosclerosis. In the present study, the direct effect of consumption of beta-casein A1 vs beta-casein A2 on atherosclerosis development was examined in a rabbit model. Sixty rabbits had their right carotid artery balloon de-endothelialised at t=0, divided randomly into 10 groups (n=6 per group), then for 6 weeks fed a diet containing 0, 5, 10 or 20% casein isolate, either beta-casein variant A1 or A2, made up to 20% milk protein with whey. Some groups had their diets supplemented with 0.5% cholesterol. Blood samples were collected at t=0, 3 and 6 weeks and rabbits were sacrificed at t=6 weeks. In the absence of dietary cholesterol, beta-casein A1 produced significantly higher (P<0.05) serum cholesterol, LDL, HDL and triglyceride levels than whey diet alone, which in turn produced higher levels than beta-casein A2. Rabbits fed beta-casein A1 had a higher percent surface area of aorta covered by fatty streaks than those fed beta-casein A2 (5.2+/-0.81 vs 1.1+/-0.39, P<0.05) and the thickness of the fatty streak lesions in the aortic arch was significantly higher (0.04+/-0.010 vs 0.00, P<0.05). Similarly, the intima to media ratio (I:M) of the balloon injured carotid arteries in A1 fed animals (0.77+/-0.07) was higher than in those that consumed A2 (0.57+/-0.04) or whey (0.58+/-0.04), but this did not reach significance. In the presence of 0.5% dietary cholesterol, the thickness of the aortic arch lesions was higher (P<0.05) in 5, 10 and 20% casein A1 fed animals compared with their A2 counterparts, while other parameters were not significantly different. It is concluded that beta-casein A1 is atherogenic compared with beta-casein A2.