Comparison of beta-ligands used in cattle production: structures, safety, and biological effects

Abstract

Technologies that increase the efficiency and sustainability of food animal production to provide meat for a growing population are necessary and must be used in a manner consistent with good veterinary practices, approved labeled use, and environmental stewardship. Compounds that bind to beta-adrenergic receptors (β-AR), termed beta-adrenergic receptor ligands (β-ligands), are one such technology and have been in use globally for many years. Though all β-ligands share some similarities in structure and function, the significance of their structural and pharmacological differences is sometimes overlooked. Structural variations in these molecules can affect absorption, distribution, metabolism, and excretion as well as cause substantial differences in biological and metabolic effects. Several β-ligands are available for use specifically in cattle production. Ractopamine and zilpaterol are beta-adrenergic agonists approved to increase weight gain, feed efficiency, and carcass leanness in cattle. They both bind to and activate β1- and β2-AR. Lubabegron is a newly developed selective beta-adrenergic modulator with unique structural and functional features. Lubabegron displays antagonistic behavior at the β1- and β2-AR but agonistic behavior at the β3-AR. Lubabegron is approved for use in cattle to reduce ammonia emissions per unit of live or carcass weight. Additionally, lubabegron can withstand prolonged use as the β3-AR lacks structural features needed for desensitization. Due to these unique features of lubabegron, this new β-ligand provides an additional option in cattle production. The individual properties of each β-ligand should be considered when making risk management decisions, as unique properties result in varying human food safety profiles that can determine appropriate safe β-ligand use.

Keywords: beta-ligand; cattle; food safety; lubabegron; ractopamine; zilpaterol.

Figure 1.

Structures of selected β-ligands.

Figure 2.

Metabolism of ractopamine.

Figure 3.

Metabolism of zilpaterol (JECFA, 2014).

Figure 4.

Metabolism of lubabegron (FDA, 2018).

Figure 5.

Metabolism of clenbuterol (JECFA, 1996).

Figure 6.

Twelve Holstein steers (200 to 250 kg BW) were fitted with permanent rumen fistulae and adapted to an 80% concentrate diet were utilized. Treatments consisted of 0.5 mg/kg lubabegron or 2.0 mg/kg ractopamine each alternately administered ruminally or post-ruminally, in a replicated (n = 3) 4 × 4 Latin Square with a 2 × 2 factorial arrangement. Blood samples were collected via jugular catheter 30 min prior to dosage and at 0.5, 1, 1.5, 2, 4, 8, 12, and 24 h post dosage. Plasma was harvested and then stored at −80 °C until assayed for nonesterified fatty acids (NEFA). Ractopamine and lubabegron doses in this study represent approximately two-times the maximum approved labeled dose for each compound.