Betaine-homocysteine methyltransferase catalyzes the methylation of homocysteine using betaine as the methyl donor (see Figure 12-1) (Finkelstein et al. 1982; Mudd and Poole, 1975; Wong and Thompson, 1972). In an alternative pathway, 5-methyltetrahydrofolate-homocysteine methyltransferase regenerates methionine by using a methyl group derived de novo from the single-carbon pool (Finkelstein et al., 1982, 1988). Methionine adenosyltransferase converts methionine to S-adenosylmethionine (the active methylating agent for many enzymatic methylations, including the methylation of phosphatidylethanolamine to form phosphatidylcholine [Ridgway and Vance, 1988]).

Perturbing the metabolism of one of the methyl donors reveals the intermingling of these metabolic pathways. Total hepatic folate content decreased by 31 to 40 percent in rats after 2 weeks on a choline-deficient diet (Selhub et al., 1991; Varela-Moreiras et al., 1995). This effect was reversed by refeeding choline (Varela-Moreiras et al., 1995). Rats fed diets deficient in both methionine and choline for 5 weeks had hepatic folate concentrations that were half of those present in controls (Home et al., 1989). Tetrahydrofolate deficiency in rats, induced by treatment with methotrexate (Barak and Kemmy, 1982; Barak et al., 1984; Freeman-Narrod et al., 1977; Pomfret et al., 1990; Svardal et al., 1988) or by dietary folate deficiency (Kim et al., 1994) resulted in diminished hepatic total choline, with the greatest decrease occurring in hepatic phosphocholine concentrations. During choline deficiency in rats, hepatic S-adenosylmethionine concentrations also decreased by as much as 50 percent (Barak et al., 1982; Poirier et al., 1977; Shivapurkar and Poirier, 1983; Zeisel et al., 1989). In rats choline deficiency for 2 weeks doubled plasma homocysteine levels (Varela-Moreiras et al., 1995). See Chapters 7 and 8 for more information on plasma homocysteine.

Males may have a higher choline requirement than do females. Female rats are less sensitive to choline deficiency than are male rats (Tessitore et al., 1995), perhaps because of females’ enhanced capacity to form the choline moiety de novo. Females rats have greater phosphatidylethanolamine-N-methyltransferase activity in liver than do males (Arvidson, 1968; Bjornstad and Bremer, 1966; Lyman et al., 1971). Estimates of the amount of increased activity vary between 10 (Lyman et al., 1971) and 50 percent (Bjornstad and Bremer, 1966). A woman’s capacity to form the choline moiety