Carnosine (β-alanyl-L-histidine, CAR) is the archetype of a class of histidine dipeptides (HP) such as balenine (N-β-alanyl-1-methyl-histidine), homocarnosine (N-4-aminobutyryl-l-histidine, HCAR) and anserine (N-β-alanyl-3-methyl-l-histidine, ANS), widely distributed in the vertebrates, and particularly abundant in the skeletal muscles and excitable tissues. Although CAR has been discovered at the beginning of the last century, its biological role is not yet clarified. However, several pharmacological properties have been up to now reported, such as anti-ischemic, anti-aging and hypoglycemic activities, effects on SNC and in particular on behavior, and preventing/protective efficacy towards diseases related to diabetes and metabolic distress syndrome, such as nephropathy and cardiovascular diseases. Hence, CAR is a promising bioactive agent, and its interest is further sustained by considering the lack of acute and chronic toxicity and that it can be assumed by ingesting a portion of beef. However, only few studies regarding the ADME properties of CAR and His derivatives have been addressed, and most of all conducted in rodents, species lack serum carnosinases, which is supposed to be primarily involved in the metabolic fate of CAR in humans. Hence, aim of the present study was first to monitor the plasma and urine levels of HP after an oral intake of CAR or food containing CAR by an high sensitive and specific HPLC-ESI-MS/MS method set-up and applied in this study. The results show that only a negligible amount of carnosine was detected in plasma after ingesting different types of meat, however, in some cases, plasma anserine concentration was significantly increased as well as urinary carnosine and anserine levels. The fact that no CAR was detected in plasma, clearly due to its fast renal clearance, makes difficult to explain the well-known role of this HP (Aldini 2002; Aldini 2002; Carini 2003; Biofactors 2005; Orioli 2005) as quencher of reactive and cytotoxic carbonyl species, generated by lipooxidation, in vivo. Hence, as second step, to gain a deeper insight into the mechanism of action, we used CAR as a model to start a molecular modelling approach for designing and developing novel drug candidates which, maintaining the trapping activity, and safety of the parent compound, will result more resistant to the enzymatic hydrolysis catalysed by serum carnosinases. The lead compound D-carnosine was evaluated, in parallel to L-CAR, for its carbonyl quenching activity and plasma stability in vitro, as well as for its pharmacokinetics profile in rats.

Bioactive histidine dipeptides: adme studies by lc-ms/ms in humans as a tool for developing new derivatives / M. Orioli, G. Aldini, M. Carini - In: Atti del congresso: 5th MS-Pharmaday 2008[s.l] : Società Chimica Italiana, 2008. - pp. 15-15 (( Intervento presentato al 5. convegno MS-Pharmaday tenutosi a Verona nel 2008.

Bioactive histidine dipeptides: adme studies by lc-ms/ms in humans as a tool for developing new derivatives

M. Orioli
;
G. Aldini
Secondo
;
M. Carini
Ultimo
2008

Abstract

Carnosine (β-alanyl-L-histidine, CAR) is the archetype of a class of histidine dipeptides (HP) such as balenine (N-β-alanyl-1-methyl-histidine), homocarnosine (N-4-aminobutyryl-l-histidine, HCAR) and anserine (N-β-alanyl-3-methyl-l-histidine, ANS), widely distributed in the vertebrates, and particularly abundant in the skeletal muscles and excitable tissues. Although CAR has been discovered at the beginning of the last century, its biological role is not yet clarified. However, several pharmacological properties have been up to now reported, such as anti-ischemic, anti-aging and hypoglycemic activities, effects on SNC and in particular on behavior, and preventing/protective efficacy towards diseases related to diabetes and metabolic distress syndrome, such as nephropathy and cardiovascular diseases. Hence, CAR is a promising bioactive agent, and its interest is further sustained by considering the lack of acute and chronic toxicity and that it can be assumed by ingesting a portion of beef. However, only few studies regarding the ADME properties of CAR and His derivatives have been addressed, and most of all conducted in rodents, species lack serum carnosinases, which is supposed to be primarily involved in the metabolic fate of CAR in humans. Hence, aim of the present study was first to monitor the plasma and urine levels of HP after an oral intake of CAR or food containing CAR by an high sensitive and specific HPLC-ESI-MS/MS method set-up and applied in this study. The results show that only a negligible amount of carnosine was detected in plasma after ingesting different types of meat, however, in some cases, plasma anserine concentration was significantly increased as well as urinary carnosine and anserine levels. The fact that no CAR was detected in plasma, clearly due to its fast renal clearance, makes difficult to explain the well-known role of this HP (Aldini 2002; Aldini 2002; Carini 2003; Biofactors 2005; Orioli 2005) as quencher of reactive and cytotoxic carbonyl species, generated by lipooxidation, in vivo. Hence, as second step, to gain a deeper insight into the mechanism of action, we used CAR as a model to start a molecular modelling approach for designing and developing novel drug candidates which, maintaining the trapping activity, and safety of the parent compound, will result more resistant to the enzymatic hydrolysis catalysed by serum carnosinases. The lead compound D-carnosine was evaluated, in parallel to L-CAR, for its carbonyl quenching activity and plasma stability in vitro, as well as for its pharmacokinetics profile in rats.
Settore CHIM/08 - Chimica Farmaceutica
2008
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/146027
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