Table 1.

Main effect of first pass metabolism of dietary phenolic compounds in human serum albumin (HSA) binding.

Class	Subclass	Reaction	Effect	References
Flavonoids	Flavonols	Hydroxylation	The binding affinity of flavonols for HSA * is structure-dependent, increasing with the number of OH groups in the A, B ring.	[33,34,35]
		Glucuronidation	Decrease the binding constants.	[36,37]
		Sulfation	Decrease the binding constants.	[38]
	Flavones	Hydroxylation	The HSA affinity of flavones was influenced by the location and number of the OH group.	[33,35,39,40]
		Hydrogenation	Hydrogenation of the unsaturated C2=C3 double bond can reduce binding affinities for CHPP **.
		Methoxylation	This reaction enhanced hydrophobicity and hydrophobic interactions increasing affinity for HSA.	[33,35,40]
	Isoflavones	Hydroxylation	The hydroxylation at positions 5 and 7 on the A ring increased HSA binding affinity rates. A weakening of isoflavones binding affinities for CHPP after of hydroxylation in C-5 (A ring) and C-3’ (B ring).	[33,35]
	Flavanones	Hydrogenation	The C2=C3 double bond conjugated with the oxo group at C-4 plays an important role in flavanone affinity for plasma proteins.	[40]
		Hydroxylation	Affinity increased by the addition of a hydroxyl group on the A ring (C-5 and C-7) and the B ring (C-2’).	[35]
		Methoxylation	Slightly increased the protein binding rate.	[40]
		Glucuronidation	Glucuronidation in the B-ring weakly destabilizes the flavanone-HSA complex.	[41]
	Flavan-3-ols	Hydroxylation	The number of hydroxyl groups on the B ring and the presence of a galloyl (3,4,5-trihydroxybenzoyl) moiety increase binding affinities for HSA.	[42,43,44]
	Anthocyanidins	Hydroxylation	The binding affinities increase with the number of hydroxyl groups on the B ring.	[45,46,47]
		Methoxylation	The methoxylation could either strengthen or reduce the anthocyanin affinity for HSA.	[46,47]
Phenolic Acids	Hydroxybenzoic acids	Hydroxylation	In the case of benzoic acid, the introduction of (1) an OH group at C-2 on the benzene ring exerted a positive effect and (2) a hydroxy substituent at C-4 had a negative influence.	[48]
		Methoxylation	Both methylation of the hydroxy groups and substituting the hydroxy groups with methyl groups at C-3 and C-4 on the benzene ring resulted in an increase of binding affinity.
	Hydroxycinnamic acids		Minimal modifications of the chemical structure led to significant changes in binding.	[49,50,51,52]
Stilbenes		Hydroxylation	The stilbenoid–HSA affinity was increased.	[35,53]
		Methylation	The stilbenoid–HSA affinity was reduced.	[54]
		Methoxylation		[53]
Hydrolysable Tannins		Hydroxylation	The intensity of the interaction depends not only on the number of OH groups, but also on the bulk, flexibility and hydrophobicity of the chemical structure.	[55,56]

* HSA: human serum albumin; ** CHPP: common human plasma protein.