Regulatory mechanisms of hepatic protein metabolism and gene expression mediated by amino acids and vitamin B₆ were investigated. 1) Rats were nourished by total parenteral nutrition, and the effects of variations in the amino acid supply on the rates of hepatic protein synthesis and degradation were investigated. Amino acids decreased the rate of degradation whilst the rate of synthesis was relatively unaffected. Protein degradation, therefore, predominates the regulation of liver protein mass. 2) Studies on cystathionase and aspartate aminotransferase (AspAT) in the liver of vitamin B₆-deficient rats showed that their rates of synthesis and degradation were both increased. The enhanced degradation was caused by different susceptibilities of apo- and holo-enzymes to lysosomal proteolysis. 3) Pyridoxal phosphate (PLP) was found to modulate AspAT gene expression by preventing the glucocorticoid receptor from binding to glucocorticoid-responsive elements. PLP also modulated albumin gene expression by inactivat ng the DNA-binding activity of tissue-specific transcriptional factors such as HNF-1 and C/EBP. 4) Amino acid vinfusion increased the albumin mRNA level and decreased the PLP concentration. The decrease in PLP concentration would prevent the inactivation of tissue-specific transcription factors and enhance albumin gene expression. The present study sheds new light on the physiological role of PLP as a mediator of gene regulation in protein/amino acid nutrition.