RETSAT

Summary

RETSAT (retinol saturase, HGNC:25991) is a protein-coding gene on chromosome 2p11.2, encoding All-trans-retinol 13,14-reductase (Q6NUM9). Catalyzes the saturation of all-trans-retinol to all-trans-13,14-dihydroretinol.

Predicted to enable all-trans-retinol 13,14-reductase activity. Predicted to be involved in retinol metabolic process. Located in membrane.

Source: NCBI Gene 54884 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 145 total
• MANE Select transcript: NM_017750

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25991
Approved symbol	RETSAT
Name	retinol saturase
Location	2p11.2
Locus type	gene with protein product
Status	Approved
Aliases	FLJ20296
Ensembl gene	ENSG00000042445
Ensembl biotype	protein_coding
OMIM	617597
Entrez	54884

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 15 protein_coding, 2 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000295802, ENST00000409984, ENST00000429806, ENST00000438611, ENST00000449375, ENST00000482694, ENST00000490291, ENST00000910001, ENST00000910002, ENST00000910003, ENST00000910004, ENST00000910005, ENST00000910006, ENST00000910007, ENST00000910008, ENST00000910009, ENST00000910010, ENST00000942520, ENST00000942521

RefSeq mRNA: 1 — MANE Select: NM_017750 NM_017750

CCDS: CCDS1972

Canonical transcript exons

ENST00000295802 — 11 exons

Exon	Start	End
ENSE00001004539	85343999	85344165
ENSE00001004540	85345975	85346094
ENSE00001004541	85350040	85350241
ENSE00001275092	85350780	85351021
ENSE00001275099	85351680	85351862
ENSE00001303755	85349384	85349581
ENSE00001829317	85354336	85354528
ENSE00003609958	85344239	85344348
ENSE00003671743	85343639	85343798
ENSE00003679509	85341955	85343381
ENSE00003681388	85344594	85344732

Expression profiles

Bgee: expression breadth ubiquitous, 284 present calls, max score 98.02.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 18.6050 / max 475.0742, expressed in 1797 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
29394	14.1070	1781
29395	3.2402	1422
29397	0.8383	454
29396	0.4195	196

Top tissues by expression

291 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
mucosa of transverse colon	UBERON:0004991	98.02	gold quality
ileal mucosa	UBERON:0000331	97.94	gold quality
jejunal mucosa	UBERON:0000399	97.79	gold quality
rectum	UBERON:0001052	97.42	gold quality
duodenum	UBERON:0002114	97.24	gold quality
subcutaneous adipose tissue	UBERON:0002190	97.21	gold quality
adipose tissue	UBERON:0001013	97.19	gold quality
right adrenal gland cortex	UBERON:0035827	96.52	gold quality
right adrenal gland	UBERON:0001233	96.43	gold quality
left adrenal gland	UBERON:0001234	96.37	gold quality
left adrenal gland cortex	UBERON:0035825	96.21	gold quality
connective tissue	UBERON:0002384	96.17	gold quality
adipose tissue of abdominal region	UBERON:0007808	96.17	gold quality
transverse colon	UBERON:0001157	96.11	gold quality
omental fat pad	UBERON:0010414	96.06	gold quality
peritoneum	UBERON:0002358	96.02	gold quality
adrenal cortex	UBERON:0001235	95.97	gold quality
colonic mucosa	UBERON:0000317	95.92	gold quality
right lobe of liver	UBERON:0001114	95.75	gold quality
small intestine Peyer’s patch	UBERON:0003454	95.72	gold quality
right lobe of thyroid gland	UBERON:0001119	95.61	gold quality
left lobe of thyroid gland	UBERON:0001120	95.58	gold quality
mucosa of sigmoid colon	UBERON:0004993	95.46	gold quality
small intestine	UBERON:0002108	95.42	gold quality
adrenal gland	UBERON:0002369	95.28	gold quality
gastrocnemius	UBERON:0001388	95.23	gold quality
thyroid gland	UBERON:0002046	94.82	gold quality
skin of leg	UBERON:0001511	94.64	gold quality
muscle of leg	UBERON:0001383	94.61	gold quality
skin of abdomen	UBERON:0001416	94.58	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): PPARA

miRNA regulators (miRDB)

59 targeting RETSAT, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-548D-3P	99.87	70.67	4362
HSA-MIR-548BB-3P	99.86	70.58	4354
HSA-MIR-548AC	99.84	70.77	4351
HSA-MIR-548H-3P	99.84	70.80	4349
HSA-MIR-548Z	99.84	70.80	4349
HSA-MIR-204-5P	99.79	71.62	2439
HSA-MIR-211-5P	99.79	71.65	2440
HSA-MIR-623	99.76	68.16	1170
HSA-MIR-3617-5P	99.75	69.41	1968
HSA-MIR-641	99.75	69.35	1975
HSA-MIR-4446-5P	99.72	69.19	2544
HSA-MIR-4755-5P	99.71	70.34	2716
HSA-MIR-5006-3P	99.71	70.26	2728
HSA-MIR-105-5P	99.54	69.24	2060
HSA-MIR-7853-5P	99.54	69.30	2055
HSA-MIR-12123	99.52	71.79	2990
HSA-MIR-21-5P	99.46	70.54	1035
HSA-MIR-513A-3P	99.39	70.63	3620
HSA-MIR-513C-3P	99.39	70.63	3620
HSA-MIR-190B-3P	99.33	68.29	1382
HSA-MIR-590-5P	99.25	70.76	930

Literature-anchored findings (GeneRIF, showing 3)

• RetSat plays an important role in the biology of adipocytes, where it favors normal differentiation, yet is reduced in the obese state. (PMID:19139408)
• RETSAT associates with DDX39B to promote fork restarting and resistance to gemcitabine based chemotherapy in pancreatic ductal adenocarcinoma. (PMID:36109793)
• Intestinal retinol saturase is implicated in the development of obesity and epithelial homeostasis upon injury. (PMID:38895981)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	retsat.2	ENSDARG00000018600
danio_rerio	retsat.1	ENSDARG00000070140
mus_musculus	Retsat	ENSMUSG00000056666
rattus_norvegicus	Retsat	ENSRNOG00000014090

Paralogs (2): PYROXD2 (ENSG00000119943), BLOC1S2 (ENSG00000196072)

Protein

Protein identifiers

All-trans-retinol 13,14-reductase — Q6NUM9 (reviewed: Q6NUM9)

Alternative names: All-trans-13,14-dihydroretinol saturase, PPAR-alpha-regulated and starvation-induced gene protein

All UniProt accessions (5): Q6NUM9, H0YGU3, H7BZ16, H7BZ81, H7C3J0

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the saturation of all-trans-retinol to all-trans-13,14-dihydroretinol. Does not exhibit any activity toward all-trans-retinoic acid, nor 9-cis, 11-cis or 13-cis-retinol isomers. May play a role in the metabolism of vitamin A. Independently of retinol conversion, may regulate liver metabolism upstream of MLXIPL/ChREBP. May play a role in adipocyte differentiation.

Subcellular location. Endoplasmic reticulum membrane.

Tissue specificity. Expressed in liver; expression positively correlates with obesity and liver steatosis. Expressed in adipose tissue; expression tends to be decreased in obese versus lean individuals.

Similarity. Belongs to the carotenoid/retinoid oxidoreductase family. CrtISO subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q6NUM9-1	1	yes
Q6NUM9-2	2

RefSeq proteins (1): NP_060220* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR036188	FAD/NAD-bd_sf	Homologous_superfamily
IPR052206	Retinol_saturase	Family

Pfam: PF13450

Catalyzed reactions (Rhea), 1 shown:

• all-trans-13,14-dihydroretinol + A = all-trans-retinol + AH2 (RHEA:19193)

UniProt features (10 total): sequence variant 3, sequence conflict 3, splice variant 2, signal peptide 1, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6NUM9-F1	95.17	0.90

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-975634	Retinoid metabolism and transport

MSigDB gene sets: 161 (showing top): GOMF_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_THE_CH_CH_GROUP_OF_DONORS, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, ACEVEDO_NORMAL_TISSUE_ADJACENT_TO_LIVER_TUMOR_DN, GOBP_REGULATION_OF_HORMONE_LEVELS, GOBP_RETINOL_METABOLIC_PROCESS, ICHIBA_GRAFT_VERSUS_HOST_DISEASE_35D_DN, GOBP_LIPID_METABOLIC_PROCESS, CHARAFE_BREAST_CANCER_LUMINAL_VS_BASAL_DN, chr2p11, MARIADASON_REGULATED_BY_HISTONE_ACETYLATION_UP, IVANOVA_HEMATOPOIESIS_EARLY_PROGENITOR, WENG_POR_TARGETS_GLOBAL_DN, WENG_POR_DOSAGE, GOBP_ISOPRENOID_METABOLIC_PROCESS, GOBP_PRIMARY_ALCOHOL_METABOLIC_PROCESS

GO Biological Process (3): retinol metabolic process (GO:0042572), retinoid metabolic process (GO:0001523), lipid metabolic process (GO:0006629)

GO Molecular Function (2): all-trans-retinol 13,14-reductase activity (GO:0051786), oxidoreductase activity (GO:0016491)

GO Cellular Component (5): nuclear outer membrane (GO:0005640), endoplasmic reticulum membrane (GO:0005789), membrane (GO:0016020), nuclear membrane (GO:0031965), endoplasmic reticulum (GO:0005783)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Visual phototransduction	1
Metabolism of fat-soluble vitamins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
nuclear outer membrane-endoplasmic reticulum membrane network	2
organelle membrane	2
retinoid metabolic process	1
primary alcohol metabolic process	1
hormone metabolic process	1
olefinic compound metabolic process	1
diterpenoid metabolic process	1
primary metabolic process	1
oxidoreductase activity, acting on the CH-CH group of donors	1
retinol metabolic process	1
catalytic activity	1
nuclear membrane	1
organelle outer membrane	1
endoplasmic reticulum subcompartment	1
cellular anatomical structure	1
nucleus	1
nuclear envelope	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

1493 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RETSAT	BCO1	Q9HAY6	539
RETSAT	LRAT	O95237	518
RETSAT	BCO2	Q9BYV7	439
RETSAT	FAXDC2	Q96IV6	419
RETSAT	ELMOD3	Q96FG2	401
RETSAT	HSD17B10	Q99714	399
RETSAT	IDI1	Q13907	399
RETSAT	DHRS4	Q9BTZ2	397
RETSAT	FDFT1	P37268	383
RETSAT	AASDH	Q4L235	375
RETSAT	GGPS1	O95749	374
RETSAT	ASGR2	P07307	372
RETSAT	SORD	Q00796	367
RETSAT	MVD	P53602	363
RETSAT	CREG1	O75629	362

IntAct

135 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
ANKRD46	ATRN	psi-mi:“MI:0914”(association)	0.640
GDPD5	GOLIM4	psi-mi:“MI:0914”(association)	0.530
SPINT2	UPK3BL1	psi-mi:“MI:0914”(association)	0.530
EVA1C	UPK3BL1	psi-mi:“MI:0914”(association)	0.530
KCNS3	UPK3BL1	psi-mi:“MI:0914”(association)	0.530
PCDHB16	UPK3BL1	psi-mi:“MI:0914”(association)	0.530
SCN3B	ABCC5	psi-mi:“MI:0914”(association)	0.530
IL9R	RETSAT	psi-mi:“MI:0914”(association)	0.530
CXCR4	TMEM120B	psi-mi:“MI:0914”(association)	0.530
SLC31A1	C2orf72	psi-mi:“MI:0914”(association)	0.530
LRRTM1	UPK3BL1	psi-mi:“MI:0914”(association)	0.530
EVA1C	STK25	psi-mi:“MI:0914”(association)	0.530
SLC31A1	PRORP	psi-mi:“MI:0914”(association)	0.530
	ESYT2	psi-mi:“MI:0914”(association)	0.350
HSCB	RBP5	psi-mi:“MI:0914”(association)	0.350
LRRTM1	TMEM223	psi-mi:“MI:0914”(association)	0.350
PCDHGB4	FAM171A2	psi-mi:“MI:0914”(association)	0.350
TMPRSS3	UPK3BL1	psi-mi:“MI:0914”(association)	0.350
TPRA1	BMPR1B	psi-mi:“MI:0914”(association)	0.350

BioGRID (167): RETSAT (Affinity Capture-MS), RETSAT (Affinity Capture-MS), RETSAT (Affinity Capture-MS), RETSAT (Affinity Capture-MS), RETSAT (Affinity Capture-MS), RETSAT (Affinity Capture-MS), RETSAT (Affinity Capture-MS), RETSAT (Affinity Capture-MS), RETSAT (Affinity Capture-MS), RETSAT (Affinity Capture-MS), RETSAT (Affinity Capture-MS), RETSAT (Affinity Capture-MS), RETSAT (Affinity Capture-MS), RETSAT (Affinity Capture-MS), RETSAT (Affinity Capture-MS)

ESM2 similar proteins: A0JPE9, A2AJL3, A2VD33, O46504, O75191, P12276, P12785, P13439, P17256, P19096, P31754, Q08D86, Q0IH28, Q0VFE7, Q3MIF4, Q3SYZ6, Q3TNA1, Q4V831, Q4V9P6, Q503J2, Q566S6, Q5M7T9, Q5R979, Q5RFE6, Q5U5V2, Q5XH07, Q5XIG6, Q5ZMJ4, Q64FG0, Q68FH4, Q6DCD1, Q6DH69, Q6GMR7, Q6GP95, Q6NUM9, Q6NUW9, Q6ZS86, Q71SP7, Q7TSQ8, Q80SY6

Diamond homologs: A0A0A1GKA2, A0B880, A0R4S9, A1RW13, A3CXS4, A3MWF6, A4FWG7, A4WKY7, A4YIV7, A6UPZ7, A6UV59, A6VGT9, A7EWL8, A7HMY3, A8NSD1, A8ZVP3, A9A9W1, A9RHW6, A9RHX1, A9SMC8, A9SME1, B0R884, B1YDX0, C3MQY1, C3MWW9, C3N6N6, C3N749, C3NGI6, C4KIA7, C4XIR5, C5X2M4, C5XNN6, D4GSS5, F6BCS4, F6H7K5, F6H9A9, G5EAZ2, H8ZPX1, O27657, O29556

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 154 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
R-HSA-425393	9	12.0×	6e-06
SLC-mediated transmembrane transport	14	8.5×	3e-07
Transport of small molecules	18	4.7×	6e-06

GO biological processes:

GO term	Partners	Fold	FDR
potassium ion import across plasma membrane	5	14.3×	3e-03
chloride transmembrane transport	6	11.1×	2e-03
monoatomic ion transport	8	9.8×	4e-04
potassium ion transmembrane transport	9	9.6×	2e-04
transmembrane transport	7	9.2×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

145 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	107
Likely benign	8
Benign	6

Top pathogenic / likely-pathogenic (0)

SpliceAI

1763 predictions. Top by Δscore:

Variant	Effect	Δscore
2:85344048:T:TA	donor_gain	1.0000
2:85344592:A:AC	donor_gain	1.0000
2:85344592:ACG:A	donor_gain	1.0000
2:85344593:C:CC	donor_gain	1.0000
2:85344593:CG:C	donor_gain	1.0000
2:85344593:CGC:C	donor_gain	1.0000
2:85346092:CAC:C	acceptor_gain	1.0000
2:85346095:C:CC	acceptor_gain	1.0000
2:85349579:CAC:C	acceptor_gain	1.0000
2:85350779:CCT:C	donor_gain	1.0000
2:85350781:TTA:T	donor_gain	1.0000
2:85350797:A:AC	donor_gain	1.0000
2:85350798:C:CC	donor_gain	1.0000
2:85350814:T:A	donor_gain	1.0000
2:85350817:T:TA	donor_gain	1.0000
2:85351017:GATTC:G	acceptor_gain	1.0000
2:85351018:ATTC:A	acceptor_gain	1.0000
2:85351019:TTC:T	acceptor_gain	1.0000
2:85351019:TTCCT:T	acceptor_loss	1.0000
2:85351020:TC:T	acceptor_gain	1.0000
2:85351021:CC:C	acceptor_gain	1.0000
2:85351022:C:CC	acceptor_gain	1.0000
2:85351674:CCTTA:C	donor_loss	1.0000
2:85351675:CTTAC:C	donor_loss	1.0000
2:85351676:TTAC:T	donor_loss	1.0000
2:85351677:TA:T	donor_loss	1.0000
2:85351678:A:C	donor_loss	1.0000
2:85351679:C:A	donor_loss	1.0000
2:85351859:AAAG:A	acceptor_gain	1.0000
2:85351863:C:CC	acceptor_gain	1.0000

AlphaMissense

3943 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:85351810:A:C	S75R	0.991
2:85351810:A:T	S75R	0.991
2:85351812:T:G	S75R	0.991
2:85351687:A:C	F116L	0.987
2:85351687:A:T	F116L	0.987
2:85351689:A:G	F116L	0.987
2:85350941:A:G	W146R	0.986
2:85350941:A:T	W146R	0.986
2:85350825:A:C	F184L	0.985
2:85350825:A:T	F184L	0.985
2:85350827:A:G	F184L	0.985
2:85344629:G:C	N407K	0.984
2:85344629:G:T	N407K	0.984
2:85344677:G:C	F391L	0.983
2:85344677:G:T	F391L	0.983
2:85344679:A:G	F391L	0.983
2:85343360:C:T	G572E	0.982
2:85351016:G:C	H121D	0.981
2:85351708:A:C	F109L	0.981
2:85351708:A:T	F109L	0.981
2:85351710:A:G	F109L	0.981
2:85351021:C:T	G119E	0.980
2:85351745:T:A	E97V	0.978
2:85350917:C:G	D154H	0.977
2:85343376:C:G	D567H	0.976
2:85350050:G:C	F263L	0.975
2:85350050:G:T	F263L	0.975
2:85350052:A:G	F263L	0.975
2:85343381:C:A	G565V	0.974
2:85351751:A:T	V95E	0.974

dbSNP variants (sampled 300 via entrez): RS1000450698 (2:85351263 C>T), RS1000803859 (2:85347613 C>T), RS1000923527 (2:85346561 T>C), RS1001519607 (2:85346880 C>A), RS1001950471 (2:85347193 C>A), RS1002044230 (2:85342023 A>C), RS1002406858 (2:85354426 T>C), RS1002418200 (2:85354054 C>A), RS1002610473 (2:85352255 A>G), RS1003751454 (2:85350391 T>A), RS1003856732 (2:85354668 A>G,T), RS1003960525 (2:85341781 G>A), RS1004027782 (2:85344859 G>T), RS1004313663 (2:85348481 A>C), RS1004382356 (2:85350633 G>A,T)

Disease associations

OMIM: gene MIM:617597 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

53 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Aflatoxin B1	affects cotreatment, increases expression, affects expression	5
Benzo(a)pyrene	decreases methylation, increases expression	4
Valproic Acid	affects expression, increases expression	3
sodium arsenite	decreases expression, increases abundance	2
Air Pollutants	affects cotreatment, increases abundance, increases oxidation, decreases expression	2
Dactinomycin	affects cotreatment, increases expression, increases secretion	2
Dexamethasone	increases expression, affects cotreatment, decreases expression	2
Methyl Methanesulfonate	increases expression	2
Smoke	decreases expression, increases abundance	2
Tetrachlorodibenzodioxin	increases expression	2
Tobacco Smoke Pollution	decreases expression, increases expression	2
aristolochic acid I	increases expression	1
FR900359	affects phosphorylation	1
bisphenol F	increases expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
bisphenol A	affects cotreatment, decreases expression	1
perfluorooctanoic acid	decreases expression	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
ciglitazone	affects binding, increases expression	1
perfluoro-n-nonanoic acid	increases expression	1
K 7174	increases expression	1
nutlin 3	affects cotreatment, increases expression, increases secretion	1
ICG 001	increases expression	1
bisphenol B	increases expression	1
bisphenol S	affects cotreatment, decreases expression	1
jinfukang	increases expression, affects cotreatment	1
(+)-JQ1 compound	increases expression	1
bisphenol AF	increases expression	1
Temozolomide	increases expression	1
Sunitinib	increases expression	1

Cellosaurus cell lines

5 cell lines: 5 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_E2J2	HAP1 RETSAT (-) 1	Cancer cell line	Male
CVCL_E2J3	HAP1 RETSAT (-) 2	Cancer cell line	Male
CVCL_E2J4	HAP1 RETSAT (-) 3	Cancer cell line	Male
CVCL_E2J5	HAP1 RETSAT (-) 4	Cancer cell line	Male
CVCL_E2J6	HAP1 RETSAT (-) 5	Cancer cell line	Male

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.