HMGCoA

FIGURE 25.32 A reaction mechanism for HMGCoA reductase. Two successive NADPH-dependent reductions convert the thioester, HMGCoA, to a primary alcohol. 

A prodrag is a drug that is not by itself pharmacologically active but needs metabolic activation by an enzyme. Examples are the cytostatic cyclophosphamide, which is activated by hydroxylation catalyzed by CYP2B6, or HMGCoA reductase inhibitor, lovastatin, which contains... 

Inhibition of HMGCoA reductase and hypolipidemic effect (Qureshi and Qureshi 1992 Tomeo and Geller 1995 Parker et ah, 1993). 

Tocotrienols present in rice bran inhibit the liver microsomal enzyme HMGCoA reductase (Qureshi and Qureshi, 1992), the key enzyme involved in the endogenous synthesis of cholesterol, and this helps to lower the circulating cholesterol. Inhibition of another enzyme, ACAT (Acyl coenzyme A acyl transferase), by y-oryzanol results in lowered LDL-C synthesis and enrichment... 

As indicated in Table 1, statins, which block cholesterol biosynthesis by inhibition of hepatic HMGCoA reductase, have been used extensively to reduce LDL-C levels. At most therapeutic doses, statins marginally increase HDL levels by 5-10% [3,16]. The HDL elevation observed with statins has been highly variable and not easily extrapolated from the effects on LDL. A recent study (STELLAR) demonstrated increased HDL elevation with the use of rosuvastatin compared to simvastatin, pravastatin or atorvastatin (10% vs. 2-6%) [16,24], Although the mechanism of HDL elevation by statins is not clearly understood, it is proposed that statins enhance hepatic apoA-I synthesis [25] and decrease apoB-containing lipoproteins [26]. A number of clinical trials have demonstrated that statins reduce the risk of major coronary events. However, it is not clear if the statin-induced rise in HDL levels is an independent contributor to the reduced risk of coronary events. The observed small increase in HDL and adverse side effect profile related to liver function abnormalities and muscle toxicity limits the use of statins as monotherapy for HDL elevation [27],... 

Figure 2.14 BioPrint (partial) profile of some HMGCoA inhibitors. The two main structural classes are highlighted by a blue and purple box for both the activity fingerprint and the 2D structures.

Activators and inhibitors regulate not the amount of enzyme protein but the activity ( efficiency ) of that which is present. Two principal mechanisms of control are (i) competitive and (ii) allosteric. Competitive control (inhibition) occurs when a compound which is structurally similar to the true substrate binds to the active site of the enzyme. This is how a number of drugs and poisons bring about their effect. For example, a group of therapeutic drugs called statins are used to treat heart disease because by inhibiting a key enzyme called HMGCoA reductase, they reduce the hepatic synthesis of cholesterol and therefore the plasma concentration of that lipid. 

Oxysterol-mediated cytoxicity occurs by neaosis or apoptosis (Lizard et al, 1999 Yin et al, 2000), and can be partially prevented by Bcl2 overexpression (which inhibits caspase-3 activation and subsequent apoptosis), and by glutathione or antioxidants (Lizard et al, 1998). The mechanism of cytotoxicity is unclear but could involve an oxidative stress (Lizard et al, 1998), a direct stimulation of apoptotic cascade (Harada et al, 1997 Christ et al, 1993), a calcium rise (Spyridopoulos et al, 2001), or metabolic dysfunctions such as inhibition of HMGCoA reductase or incorporation of oxysterols into membranes (Brown and Jessup, 1999). 

Statin an inhibitor of the enzyme HMGCoA reductase (HMGR). 

Unless contraindicated, lipid lowering with HMGCoA reductase inhibitors (statins) should be used to treat hyperlipidemia for prevention of cardiovascular complications and are effective and well tolerated in those at least up to 80 years with coronary disease. 

Transcription factors Fos, Hsp70, proteinkinase C Myc, Myb, p53, Hsp70 Tyrosine aminotransferase HMGCoA rednctase... 

AcetylCoA carboxylase Glycogen synthase HMGCoA reductase NO synthase Biosynthesis of fatty adds Glycogen synthesis Biosynthesis of cholesterol Biosynthesis of NO ... 

AcetylCoA (C2) can also react with acetoacetylGoA (Cj) to generate hydroxy-methylglutarylCoA (HMGCoA) (C6) and thence the isoprenoid precursor mevalonate (C6). Mevalonate (C(i) ultimately yields the key C-, isoprenoids isopentenylpyrophosphate (CH3G(=GH2)—CH2—CH2—O—P03—P03) (IP-PP) and dimethylallylpyrophosphate (CH3— C(GH3)=GH—CH2—O—P03—P03) (DMA-PP), the immediate precursors of cholesterol and... 

Santos, A.C., and Lehmann, R. (2004). Isoprenoids control germ cell migration downstream of HMGCoA reductase. Dev Cell 6 283-293. 

HMGCoA reductase Oral agent, inhibits HMGCoA reductase LDLc 4,18-55% Potential for elevating liver... 

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